JP4842829B2 - Nitrogen-containing fused heterocyclic compounds - Google Patents

Nitrogen-containing fused heterocyclic compounds Download PDF

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JP4842829B2
JP4842829B2 JP2006538217A JP2006538217A JP4842829B2 JP 4842829 B2 JP4842829 B2 JP 4842829B2 JP 2006538217 A JP2006538217 A JP 2006538217A JP 2006538217 A JP2006538217 A JP 2006538217A JP 4842829 B2 JP4842829 B2 JP 4842829B2
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optionally substituted
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JP2007510646A (en
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アルバート・チャールズ・ギョーコス
クリストファー・ピーター・コレット
スク・ヤン・チョー
スコット・アラン・プラット
ティモシー・マーク・ターナー
倫代 業天
郡  正城
和義 麻生
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武田薬品工業株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30Nitrogen atoms not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Description

  The present invention relates to a novel nitrogen-containing fused heterocyclic compound having CRF (adrenocorticotropic hormone releasing factor) antagonistic activity and a pharmaceutical composition containing the same.

    Adrenocorticotropic hormone-releasing factor (hereinafter abbreviated as “CRF”) is a 41 amino acid neuropeptide that has been isolated and purified from the pituitary as a peptide that promotes the release of corticotropin (ACTH). It was. First, the structure was determined from the sheep hypothalamus, and then its presence was also confirmed in rats or humans, and the structure was determined (see Non-Patent Documents 1 to 3). The amino acid sequence is the same in humans and mice, but seven amino acids are different in sheep. CRF is synthesized, cleaved and secreted as the carboxy terminus of prepro CRF. CRF peptide and its mRNA are most abundant in the hypothalamus and pituitary and are widely distributed in brains such as cerebral cortex, cerebellum, hippocampus and amygdala. In peripheral tissues, its presence has been confirmed in placenta, adrenal gland, lung, liver, pancreas, skin and digestive tract (see Non-Patent Documents 4 to 7). The CRF receptor is a seven-transmembrane G protein coupled receptor, and there are two subtypes, CRF1 and CRF2. CRF1 has been reported to be present mainly in the cerebral cortex, cerebellum, olfactory bulb, pituitary gland and amygdala. On the other hand, the CRF2 receptor has two subtypes, CRF2α and CRF2β. CRF2α receptors are widely distributed in the hypothalamus, septum, and choroid plexus, and CRF2β receptors are found mainly in peripheral tissues such as skeletal muscle and distributed in brain blood vessels (non-patented). Reference 8-10). Since each receptor has a different distribution in the living body, it is understood that its role is also different (see Non-Patent Document 11).

  The physiological action of CRF is known to have an effect on the endocrine system, CRF is produced and secreted in response to stress in the hypothalamus, and acts on the pituitary to promote the release of ACTH (non-) (See Patent Document 12). In addition to its action on the endocrine system, CRF acts as a neurotransmitter or neuromodulator in the brain, integrating actions on electrophysiology, autonomic nerves and stress (see Non-Patent Documents 13 and 14). When CRF is administered to the ventricle of an experimental animal such as a rat, anxiety behavior is observed, and more anxiety behavior is observed in CRF overexpressing mice compared to normal animals (see Non-Patent Documents 15 to 17). ). Further, α-helical CRF (9-41), a peptidergic CRF receptor antagonist, exhibits an anxiolytic action in an animal model (see Non-Patent Documents 17 and 18). Rat blood pressure, heart rate and body temperature increase with stress or CRF administration, but the peptidergic CRF antagonist α-helical CRF (9-41) suppresses stress-induced increases in blood pressure, heart rate and body temperature ( Non-patent document 19). The peptidergic CRF receptor antagonist α-helical CRF (9-41) suppresses abnormal behavior due to withdrawal of dependent drugs such as alcohol and cocaine (see Non-Patent Documents 20 and 21). Furthermore, it has been reported that learning and memory are promoted by administration of CRF in rats (see Non-Patent Documents 22 to 24).

  Since CRF is related to the stress response in the living body, there are clinical reports on depression and anxiety related to stress. The CRF concentration in cerebrospinal fluid of depressed patients is higher than that of normal subjects (see Non-Patent Document 25), and the mRNA concentration of CRF in the hypothalamus of depressed patients is higher than that of normal subjects. (See Non-Patent Document 26). CRF binding sites in the cerebral cortex of patients who committed suicide due to depression have decreased (see Non-Patent Document 27). The increase in plasma ACTH concentration by CRF administration is small in depressed patients (see Non-Patent Document 28). In patients with panic disorder, the increase in plasma ACTH concentration by CRF administration is small (see Non-Patent Document 29). The CRF concentration in the cerebrospinal fluid of patients with anxiety induced by stress such as obsessive compulsive disorder, post-traumatic stress disorder, Tourette's syndrome, etc. is higher than that of normal individuals (Non-patent Documents 30- 32). The CRF concentration in cerebrospinal fluid of patients with schizophrenia is higher than that of normal subjects (see Non-patent Documents 33 and 34). Thus, it has been reported that abnormalities exist in the biological response system via CRF in psychosis involving stress.

  The effect of CRF on the endocrine system can be estimated from the characteristics of CRF transgenic animals and the behavior of experimental animals. In CRF overexpressing mice, excessive secretion of ACTH and corticosteroids occurs, and abnormalities similar to Cushing's syndrome such as muscle atrophy, alopecia, infertility, etc. are observed (see Non-patent Document 35). CRF inhibits feeding in laboratory animals such as rats (see Non-Patent Documents 36 and 37). In addition, α-helical CRF (9-41), a peptidergic CRF antagonist, suppressed a decrease in food intake due to stress load in an experimental model (see Non-Patent Document 38). CRF inhibited weight gain in hereditary obese animals (see Non-Patent Document 39). In patients with neurological eating disorders, the increase in ACTH in plasma by administration of CRF is small (see Non-Patent Document 40). It can be seen that low CRF values are associated with obesity syndrome (see Non-Patent Document 41). It was suggested that the serotonin reuptake inhibitor may suppress the feeding and reduce body weight through CRF release (see Non-Patent Document 42).

  CRF is centrally or peripherally related to gastrointestinal motility involved in stress or inflammation (see Non-Patent Document 43). CRF acts centrally or peripherally, weakens gastric contractility, and reduces gastric emptying force (see Non-Patent Documents 44 and 45). In addition, α-helical CRF (9-41), which is a peptidergic CRF antagonist, has a repairing action on a decrease in gastric function due to laparotomy (see Non-Patent Document 46). CRF suppresses the secretion of gastric bicarbonate ions, decreases gastric acid secretion, and suppresses ulcers caused by low-temperature suppression stress (see Non-Patent Document 46). Furthermore, α-helical CRF (9-41), which is a peptidergic CRF antagonist, exhibits an inhibitory action on gastric acid secretion decrease, gastric emptying decrease, small intestinal transport decrease, and colon transport enhancement due to suppressive stress (Non-patent Document 47). reference). In healthy people, mental stress increases gas and abdominal pain due to anxiety and bowel dilatation, and CRF decreases the threshold of discomfort (see Non-Patent Documents 48 and 49). In patients with irritable bowel syndrome, colonic motility is excessively enhanced by CRF administration compared to healthy individuals (see Non-Patent Document 50).

It has been reported from laboratory animal studies and clinical studies that CRF is induced by inflammation and is involved in the inflammatory response. CRF production is locally increased in inflammatory sites in experimental animals and in synovial fluid from rheumatoid arthritis patients (see Non-Patent Documents 51 to 53). CRF induces degranulation of mast cells and increases vascular permeability (see Non-Patent Documents 54 and 55). CRF can also be found in the thyroid gland of autoimmune thyroiditis patients (see Non-Patent Document 56). When CRF was administered to experimental autoimmune encephalomyelitis rats, the progression of symptoms such as paralysis was markedly inhibited (see Non-Patent Document 57). In rats, immune response activities such as T lymphocyte proliferation and natural killer cell activity are reduced by CRF administration or stress loading (see Non-Patent Document 58).
Science, 213, 1394 (1981) Proc. Natl. Acad. Sci USA, 80, 4851 (1983) EMBO J. 5, 775 (1983) J. Clin. Endocrinol. Metab., 65, 176 (1987) J. Clin. Endocrinol. Metab., 67, 768 (1988) Regul. Pept., 18, 173 (1987) Peptides, 5 (Suppl. 1), 71 (1984) J. Neurosci. 15, 6340 (1995) Endocrinology, 137, 72 (1996) Biochim. Biophys. Acta, 1352, 129 (1997) Trends. Pharmacol. Sci. 23, 71 (2002) Recent Prog. Horm. Res., 39, 245 (1983) Brain Res. Rev., 15, 71 (1990) Pharmacol. Rev., 43, 425 (1991) Brain Res., 574, 70 (1992) J. Neurosci., 10, 176 (1992) J. Neurosci., 14, 2579 (1994) Brain Res., 509, 80 (1990) J. Physiol., 460, 221 (1993) Psychopharmacology, 103, 227 (1991) Pharmacol. Rev. 53, 209 (2001) Nature, 375, 284 (1995) Neuroendocrinology, 57, 1071 (1993) Eur. J. Pharmacol., 405, 225 (2000) Am. J. Psychiatry, 144, 873 (1987) Am. J. Psychiatry, 152, 1372 (1995) Arch. Gen. Psychiatry, 45, 577 (1988) N. Engl. J. Med., 314, 1329 (1986) Am. J. Psychiatry, 143, 896 (1986) Arch. Gen. Psychiatry, 51, 794 (1994) Am. J. Psychiatry, 154, 624 (1997) Biol. Psychiatry, 39, 776 (1996) Brain Res., 437, 355 (1987) Neurology, 37, 905 (1987) Endorcrinology, 130, 3378 (1992) Life Sci., 31, 363 (1982) Neurophamacology, 22, 337 (1983) Brain Res. Bull., 17, 285 (1986) Physiol. Behav., 45, 565 (1989) J. Clin. Endocrinol. Metab., 62, 319 (1986) Endocrinology, 130, 1931 (1992) Pharmacol. Rev., 43, 425 (1991) Am. J. Physiol. Gastrointest. Liver Physiol. 280, G315 (2001) Regulatory Peptides, 21, 173 (1988) Am. J. Physiol., 253, G241 (1987) Am. J. Physiol., 258, G152 (1990) Gastroenterology, 95, 1510 (1988) Gastroenterology, 109, 1772 (1995) Neurogastroenterol. Mot., 8, 9 (1996) Gut, 42, 845 (1998) Science, 254, 421 (1991) J. Clin. Invest., 90, 2555 (1992) J. Immunol., 151, 1587 (1993) Endocrinology, 139, 403 (1998) J. Pharmacol. Exp. Ther., 288, 1349 (1999) Am. J. Pathol. 145, 1159 (1994) J. Immunil., 158, 5751 (1997) Endocrinology, 128, 1329 (1991)

As described above, a compound having a CRF receptor antagonistic action is expected to exert an excellent effect in the treatment or prevention of various diseases in which CRF is involved.
As CRF antagonists, for example, peptidic CRF receptor antagonists in which a part of the amino acid sequence of CRF of human or other mammals or related peptides has been modified or removed have been reported. [Science, 224, 889 (1984); J. Pharmacol. Exp. Ther., 269, 564 (1994); Brain Res. Rev., 15, 71 (1990)] . However, peptide derivatives have low utility as pharmaceuticals from the viewpoint of pharmacokinetics such as chemical stability and absorbability in oral administration, bioavailability, and transport function in the brain.

That is, the present invention
[1] Formula (I):
(Wherein ring A is represented by formula (A ′):
Wherein X is carbon, X 1 is oxygen, sulfur or —NR 5 — (wherein R 5 is hydrogen, optionally substituted hydrocarbyl or acyl), or formula (A ″):
(Wherein X is nitrogen, R 6 is hydrogen, optionally substituted hydrocarbyl or acyl);
R 1 is (1) an amino substituted with two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino ( Provided that the amino nitrogen of the cyclic amino has no carbonyl adjacent to the nitrogen);
R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocycle;
Y 1 , Y 2 and Y 3 are each an optionally substituted methine or nitrogen, provided that no more than one of Y 1 , Y 2 and Y 3 is nitrogen;
W is a bond, — (CH 2 ) n — or — (CH 2 ) m —CO— (wherein n is an integer of 1 to 4 and m is an integer of 0 to 4);
Z is a bond, —CO—, oxygen, sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 —alk—, —CONR 4 — or —NR 4 CO— (wherein alk is Or a salt thereof (provided that (i) ring A is a compound represented by formula (I)): an optionally substituted C 1-4 alkylene and R 4 is hydrogen, an optionally substituted hydrocarbyl or acyl). A 5-membered ring of A ′ (X is carbon and X 1 is sulfur), W is a bond, Z is —NHCO— or —CONH—, and Y 1 is CR 3a (wherein R 3a is hydrogen, halogen, or alkoxy) and (ii) ring A is a 5-membered ring of formula A ′ where X is carbon and X 1 is oxygen, sulfur or —NH—. R 1 is optionally substituted 1-piperazinyl, W is a bond And Z is a bond, and R 2 is an optionally substituted aryl));
[2] A prodrug of the compound according to [1] above;
[3] The compound of the above-mentioned [1], wherein R 1 is amino substituted with two optionally substituted C 1-4 alkyl groups;
[4] The compound of the above-mentioned [1], wherein R 1 is optionally substituted C 1-4 alkyl and optionally substituted phenyl or optionally substituted heterocyclic.
[5] The compound of the above-mentioned [1], wherein R 1 is a 5- or 6-membered cyclic amino optionally substituted with one or more substituents;
[6] Y 1 is CR 3a , Y 2 is CR 3b , and Y 3 is CR 3c (wherein R 3a , R 3b and R 3c are independently hydrogen, halogen, nitro, optionally substituted C 1-4 hydrocarbyl, an optionally substituted C 1-4 hydrocarbyloxy, optionally substituted C 1-4 hydrocarbylthio, acyl containing up to four amino optionally substituted or a carbon atom) The compound of the above-mentioned [1], which is
[7] The compound according to the above [1], wherein one of Y 1 , Y 2 and Y 3 is nitrogen;
[8] The compound according to [1] above, wherein W is a bond;
[9] The compound of the above-mentioned [1], wherein R 2 is an optionally substituted C 6-10 aryl or an optionally substituted 5- or 10-membered heterocycle;
[10] The compound of the above-mentioned [1], wherein R 2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic ring;
[11] The compound according to [1] above, wherein Z is —NR 4 — (wherein R 4 has the same meaning as in [1] above);
[12] Ring A is a thiazole ring or formula (Aa):
(Wherein R 5a is hydrogen, C 1-4 alkyl which may be substituted, or acyl containing up to 4 carbon atoms), and the imidazole ring represented by the above [1];
[13] Y 1 is CR 3a , Y 2 is CR 3b , and Y 3 is CR 3c (wherein R 3a , R 3b and R 3c are independently hydrogen, halogen or an optionally substituted hydrocarbyl. W is a bond; R 2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocycle; Z is —NR 4 — (wherein R 4 Is hydrogen or optionally substituted hydrocarbyl), the compound according to the above [1];
[14] Y 1 is CR 3a , Y 2 is CR 3b , and Y 3 is CR 3c (wherein R 3a , R 3b and R 3c are independently hydrogen, halogen, nitro, optionally substituted C 1-4 hydrocarbyl, an optionally substituted C 1-4 hydrocarbyloxy, optionally substituted C 1-4 hydrocarbylthio, acyl containing up to four amino optionally substituted or a carbon atom) W is a bond; R 2 is an optionally substituted C 6-10 aryl or an optionally substituted 5 or 10 membered heterocycle; Z is —NR 4 — (wherein R 4 is hydrogen or optionally substituted hydrocarbyl); ring A is a thiazole ring or formula (Aa):
(Wherein R 5a is hydrogen, C 1-4 alkyl which may be substituted, or acyl containing up to 4 carbon atoms), and the imidazole ring represented by the above [1];
[15] Formula (Ia):
(Wherein ring A is represented by formula (A ′):
Wherein X is carbon, X 1 is oxygen, sulfur or —NR 5 — (wherein R 5 is hydrogen, optionally substituted hydrocarbyl or acyl), or formula (A ″):
(Wherein X is nitrogen, R 6 is hydrogen, optionally substituted hydrocarbyl or acyl);
R 1a is (1) an amino substituted with two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino. Yes;
R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocycle;
Y 1 , Y 2 and Y 3 are each optionally substituted methine or nitrogen, provided that no more than one of Y 1 , Y 2 and Y 3 is nitrogen;
W is a bond, — (CH 2 ) n — or — (CH 2 ) m —CO— (wherein n is an integer of 1 to 4 and m is an integer of 0 to 4);
Z is a bond, —CO—, oxygen, sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 —alk—, —CONR 4 — or —NR 4 CO— (wherein alk is A substituted or unsubstituted C 1-4 alkylene, R 4 is hydrogen, an optionally substituted hydrocarbyl or acyl) or a salt thereof (wherein ring A is of formula A ′) 5-membered ring (X is carbon and X 1 is sulfur), W is a bond, Z is —NHCO— or —CONH—, and Y 1 is CR 3a (wherein R 3a is A method of treating or preventing a disease involving a CRF receptor, comprising administering an effective amount of a compound (except for a compound that is halogen or alkoxy) to a subject in need thereof;
[16] The treatment or prevention method according to [15] above, wherein the disease to be treated or prevented is selected from affective disorder, depression and anxiety;
[17] Use of the compound (Ia) or a salt thereof according to the above [15] for producing a preventive or therapeutic agent for a disease involving a CRF receptor;
[18] Use of the compound (Ia) or a salt thereof according to [15] above for producing a preventive or therapeutic agent for affective disorder, depression or anxiety;
[19] A prophylactic or therapeutic agent for a disease involving a CRF receptor comprising compound (Ia) or a salt thereof according to [15] above; and [20] Compound (Ia) or a salt thereof according to [15] above. A preventive or therapeutic agent for emotional disorder, depression or anxiety is provided.

As used herein, the term “hydrocarbyl” means a monovalent group containing only carbon and hydrogen.
In the above formula, ring A of formula (I) and (Ia) is represented by the following formula A ′ or A ″:

It is a 5-membered ring represented by.
In the formula (A ′), X represents carbon, and X 1 represents oxygen, sulfur or —NR 5 — (wherein R 5 is hydrogen, optionally substituted hydrocarbyl or acyl). That is, examples of the 5-membered ring of the formula (A ′) include an oxazole ring, a thiazole ring, and an imidazole ring.
As the “hydrocarbyl” of the “optionally substituted hydrocarbyl” represented by R 5 of the formula: —NR 5 —, an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic group. Hydrocarbon group, optionally substituted alicyclic-aliphatic hydrocarbon group, optionally substituted aromatic hydrocarbon group, optionally substituted aromatic-aliphatic hydrocarbon group (aralkyl group) Etc.

  Examples of the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl and the like. Saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms (eg, alkyl); and vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- Hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propiyl 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, Unsaturated aliphatic hydrocarbon groups having 2 to 8 carbon atoms such as 5-hexynyl, 2,4-hexadiynyl, 1-heptynyl, 1-octynyl (eg, alkenyl, alkynyl, alkadienyl, alkadiynyl) Group, etc.).

Examples of the alicyclic hydrocarbon group include saturated alicyclic hydrocarbon groups having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (eg, cycloalkyl group, etc.); 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadi Unsaturated alicyclic hydrocarbon groups having 3 to 7 carbon atoms such as enyl (eg, cycloalkenyl, cycloalkadienyl group, etc.); 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2 Naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1- Partially saturated condensed bicyclic hydrocarbon groups such as naphthyl and 3,4-dihydro-2-naphthyl [preferably partially saturated C 9-10 condensed bicyclic hydrocarbon groups (the benzene ring is 5 Or those bonded to a 6-membered non-aromatic cyclic hydrocarbon group). The alicyclic hydrocarbon group may be cross-linked.

Examples of the alicyclic-aliphatic hydrocarbon group include those obtained by bonding the alicyclic hydrocarbon group and the aliphatic hydrocarbon group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, Cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2- (3,4 4-14 carbons such as -dihydro-2-naphthyl) ethyl, 2- (1,2,3,4-tetrahydro-1-naphthyl) ethyl, 2- (3,4-dihydro-2-naphthyl) ethenyl those with atoms (eg, C 3-7 cycloalkyl -C 1-4 alkyl , C 3-7 cycloalkenyl -C 1-4 alkyl group, C 3-7 cycloalkyl -C 2-4 alkenyl group, C 3-7 cycloalkenyl -C 2-4 alkenyl group, partially saturated C 9 -10 condensed bicyclic hydrocarbon-C 1-4 alkyl group, partially saturated C 9-10 condensed bicyclic hydrocarbon-C 2-4 alkenyl group and the like.

Examples of the aromatic hydrocarbon group include phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl. 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro Aryl groups having 6 to 10 carbon atoms such as -4-naphthyl (including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is condensed with a phenyl group) and the like.
Examples of the aromatic-aliphatic hydrocarbon group include phenyl-C 1-4 alkyl groups such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc. Aralkyl groups having 14 carbon atoms (C 6-10 aryl-C 1-4 alkyl group); naphthyl-C 1-, such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc. 4 alkyl group; phenyl-C 2-4 alkenyl group, for example, C 6-10 aryl-C 2-4 alkenyl group such as styryl, cinnamyl and the like.

The “hydrocarbyl” group may have a substituent at a substitutable position. Examples of such substituents include halogen, nitro, cyano, oxo, (1) an optionally substituted heterocyclic group, (2) an optionally substituted sulfinyl group, and (3) an optionally substituted group. A sulfonyl group, (4) an optionally substituted hydroxyl group, (5) an optionally substituted thiol group, (6) an optionally substituted amino group, (7) an acyl group, (8) esterification or Examples thereof include a carboxyl group which may be amidated and (9) a phosphoryl group which may be substituted.
(2) the optionally substituted sulfinyl group, (3) the optionally substituted sulfonyl group, (4) the optionally substituted hydroxyl group, (5) the optionally substituted thiol group and (6 ) The substituent of the amino group which may be substituted includes optionally substituted hydrocarbyl. Examples of the “hydrocarbyl” of the optionally substituted hydrocarbyl include those exemplified above. Such hydrocarbyls may be substituted with one or more substituents at substitutable positions. Substituents on optionally substituted hydrocarbyl as substituents include halogen, nitro, cyano, hydroxyl group, thiol, amino and carboxy.

Specific examples of the optionally substituted sulfinyl group in (2) above include C 1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.) and C 6-10 arylsulfinyl. (Eg, phenylsulfinyl, naphthylsulfinyl, etc.).
Specific examples of the optionally substituted sulfonyl group in (3) above include C 1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.) and C 6-10 arylsulfonyl. (Eg, phenylsulfonyl, naphthylsulfonyl, etc.).
Specific examples of the optionally substituted hydroxyl group in (4) above include hydroxy, C 1-6 alkoxy (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy). , T-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.) and C 6-10 aryloxy (eg, phenoxy, naphthoxy, etc.).
Specific examples of the optionally substituted thiol group in (5) above include thiol, C 1-6 alkylthio (eg, methylthio, ethylthio, propylthio, etc.) and C 6-10 arylthio (eg, phenylthio, naphthylthio). Etc.).
Specific examples of the optionally substituted amino group of (6) above include amino and mono-C 1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) , Di-C 1-6 alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.) and the like.

Examples of the acyl group of (7) include the same groups as the acyl group of R 5 .
The ester group or amide group of the carboxyl group which may be esterified or amidated in the above (8) may be substituted in the same manner as the substituent of the hydroxyl group which may be substituted in the above (4). Examples thereof include an ester group having hydrocarbyl or an amide group having an optionally substituted amino group described in (6) above.
Specific examples of the carboxyl group which may be esterified include carboxy, C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C 6-10 aryl. Examples thereof include oxy-carbonyl (eg, phenoxy-carbonyl, etc.), C 7-16 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like.
Specific examples of the carboxyl group that may be amidated include carbamoyl, mono-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C 1-6 alkyl-carbamoyl (eg, Dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C 6-10 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- to 6-membered heterocyclic carbamoyl (eg, 2- And pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like.

As the “acyl” represented by R 5 of the formula: —NR 5 —, the formyl and carbonyl groups are C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-7 cyclo An alkyl group, a C 3-7 cycloalkynyl group or an aromatic group (eg, phenyl group, pyridyl group, etc.) (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, cyclobutane) Carbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, cyclohexenecarbonyl, benzoyl, etc.).
R 5 is preferably hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, more preferably hydrogen, C 1-10 alkyl.
In the formula (A ″), X represents nitrogen, and R 6 represents hydrogen, an optionally substituted hydrocarbyl or acyl.

Examples of the “optionally substituted hydrocarbyl” and “acyl” represented by R 6 include the same groups as those exemplified for the optionally substituted hydrocarbyl and acyl in R 5 .
R 6 is preferably hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, more preferably hydrogen, C 1-10 alkyl.

R 1 and R 1a in formulas (I) and (Ia) are (1) an amino substituted with two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, Or (2) an optionally substituted cyclic amino provided that the cyclic amino does not have a carbonyl adjacent to the nitrogen of formula (I). The “optionally substituted hydrocarbyl group” in the “amino substituted with two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group” is the substitution of R 5 Examples thereof include the same groups as those exemplified for the hydrocarbyl which may be used. The “optionally substituted heterocyclic group” in the “amino substituted with two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group” includes R 2 Examples of the heterocyclic group which may be substituted include the same groups as those exemplified below.
Examples of the “cyclic amino” in the “optionally substituted cyclic amino” include aziridino, pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperidino, 1,2-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, Examples include 3- to 7-membered cyclic amino groups such as piperazino, morpholino, thiomorpholino and the like. The cyclic amino group is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy-C 1-6 alkyl, C 5-7 cycloalkyl, C 6-10 aryl (the aryl is halogen , C 1-6 alkyl, halogeno C 1-6 alkyl and optionally having 1 or 2 substituents selected from C 1-6 alkoxy, C 7-14 aralkyl (wherein the aralkyl is halogen, Optionally having one or two substituents selected from C 1-6 alkyl, halogeno C 1-6 alkyl and C 1-6 alkoxy), hydroxy, hydroxy-C 1-6 alkyl, C 6-6 10 aryloxy (said aryloxy, halogen, C 1-6 alkyl, 1 or 2 substituents selected from halogeno C 1-6 alkyl and C 1-6 alkoxy May have), C 7 - 14 aralkyloxy, C 6-10 aryl - carbonyl, carboxyl, C 1-6 alkoxy - carbonyl, carbamoyl, C 6-10 aryl - carbamoyl, amino, C 6-10 A group consisting of aryl-carbonylamino, C 1-6 alkyl-carbonylamino, C 1-6 alkoxy-carbonylamino, C 6-10 arylthio, C 6-10 arylsulfonyl, cyano, 5-7 membered heterocyclic group and oxo (The oxo group is not substituted at the position adjacent to the nitrogen bonded to W of formula (I)).

Among them, R 1 and R 1a in formulas (I) and (Ia) are preferably substituted with two substituents selected from optionally substituted C 1-4 alkyl and optionally substituted phenyl. Amino, more preferably amino substituted with two optionally substituted C 1-4 alkyl groups. The optionally substituted C 1-4 alkyl group and optionally substituted phenyl are preferably unsubstituted or hydroxy, C 1-4 alkoxy; amino, mono or di-C 1-4 It is substituted with a group selected from the group consisting of alkylamino; halogen; and pyridyl.

R 2 in formulas (I) and (Ia) is alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocycle. is there.
As the “alkyl” for R 2 , C 1 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl and the like. A -8 alkyl group is mentioned.
“Cycloalkyl” in “optionally substituted cycloalkyl” for R 2 includes C 3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
“Cycloalkenyl” of “optionally substituted cycloalkenyl” for R 2 includes 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl. C 3-7 cycloalkenyl groups such as 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and the like.

The “aryl” in the “optionally substituted aryl” for R 2 includes phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5, 6, 7 , 8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3 -Aryl groups having 6 to 10 carbon atoms such as naphthyl and 5,6-dihydro-4-naphthyl (including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is condensed with a phenyl group) and the like .

As the “heterocycle” of the “optionally substituted heterocycle” of R 2 , (i) a 5- to 7-membered heterocyclic group containing one sulfur atom, one nitrogen atom or one oxygen atom (Ii) a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, and (iii) a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom, etc. Is mentioned. In addition, each of the heterocyclic groups exemplified in (i) to (iii) may be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be aromatic or non-aromatic. There may be.
Examples of the heterocyclic ring which may be substituted for R 2 include an aromatic monocyclic heterocyclic group and a non-aromatic heterocyclic group.
Specific examples of the heterocyclic ring that may be substituted include (i) aromatic monocyclic heterocyclic groups (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl) 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.) and (ii) non-aromatic heterocyclic groups (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl) , Pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl , Morpholinyl, thiomorpholinyl, piperazinyl and the like.

The in R 2 "cycloalkyl", "cycloalkenyl", "aryl" and "heterocycle" may have the same substituents as those exemplified for the hydrocarbyl substituted for R 5 Furthermore, R 5 may have the same group as the optionally substituted hydrocarbyl as those substituents.
Two substituents of R 2 may be bonded to each other to form a ring. Examples of such rings include aromatic condensed heterocyclic groups such as 8- to 12-membered aromatic condensed heterocyclic groups (preferably the above 5- or 6-membered aromatic monocyclic heterocyclic ring condensed with a benzene ring. A heterocyclic group comprising a group, or a heterocyclic group comprising the 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different 5- or 6-membered aromatic monocyclic heterocyclic group (eg, benzofuranyl) , Isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purini , Pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthenyl, phenathidinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolinyl [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1 2,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like.
Among them, R 2 is preferably an optionally substituted phenyl or an optionally substituted 5- to 6-membered heterocyclic group.

In formulas (I) and (Ia), Y 1 is CR 3a or nitrogen, Y 2 is CR 3b or nitrogen, Y 3 is CR 3c or nitrogen (wherein R 3a , R 3b and R 3c are independently hydrogen , Halogen, nitro, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, optionally substituted amino or acyl), wherein Y 1 , One or less of Y 2 and Y 3 is nitrogen.
The 6-membered ring having Y 1 , Y 2 and Y 3 in the formulas (I) and (Ia) is a ring containing 1 or less nitrogen such as a benzene ring and a pyridine ring.

Examples of the halogen include fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
Examples of the “ optionally substituted hydrocarbyl” in R 3a , R 3b and R 3c include the same groups as those exemplified for the optionally substituted hydrocarbyl of R 5 .
The “hydrocarbyl” of the “optionally substituted hydrocarbyloxy” and “optionally substituted hydrocarbylthio” of R 3a , R 3b and R 3c is exemplified for the optionally substituted hydrocarbyl of R 5. The same groups as those mentioned above.
Examples of the “ optionally substituted amino” for R 3a , R 3b and R 3c include an amino group, an N-mono-substituted amino group, and an N, N-di-substituted amino group. Examples of the substituted amino group include an optionally substituted hydrocarbyl group (eg, C 1-8 alkyl group, C 3-7 cycloalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3- 7 cycloalkenyl group, C 6-10 aryl group optionally having C 1-4 alkyl group), optionally substituted heterocyclic group (eg, R 2 optionally substituted heterocycle) similar group), or formula and groups: -COR 3d (wherein, R 3d is "substituted .R 3d represents a hydrogen atom or an optionally substituted hydrocarbylcarbonyl group or an optionally substituted heterocyclic group The “hydrocarbyl group” or “heterocyclic group” in the “optionally substituted hydrocarbyl group” or “optionally substituted heterocyclic group” is the same as R 5 “optionally substituted hydrocarbyl” or R 2 “ Replaced There may have the same substituent as substituent for "hydrocarbylcarbonyl group" or "heterocyclic group" in even heterocyclic group "in), preferably C 1-10 acyl (e.g., C 2-7 alkanoyl Benzoyl, nicotinoyl, etc.). Specific examples thereof include methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino. , Nicotinoylamino and the like.
Further, two substituents in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (eg, piperidino, piperazino, morpholino, thiomorpholino, etc.).

Examples of the acyl of R 3a , R 3b and R 3c include the same groups as those exemplified for the acyl of R 5 .
In formulas (I) and (Ia), Y 1 , Y 2 and Y 3 are preferably CR 3a , CR 3b and CR 3c , respectively. R 3a , R 3b and R 3c are preferably hydrogen, C 1-4 alkyl and C 1-4 alkoxy.

In the formulas (I) and (Ia), W is a bond, — (CH 2 ) n — or — (CH 2 ) m —CO—, where n is 1 to 4 and m is 0 to 4. Preferably, W is a bond.
In the formulas (I) and (Ia), Z represents a bond, —CO—, oxygen, sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 —alk—, —CONR 4 — or —. NR 4 is CO-.
The alk is optionally substituted C 1-4 alkylene such as methylene, ethylene, propylene, butylene and the like.
R 4 is hydrogen, optionally substituted hydrocarbyl or acyl. "Hydrocarbyl optionally substituted" and the R 4 "acyl" includes the same groups as those exemplified for the optionally substituted hydrocarbyl group and acyl R 5.
Preferably, Z is —NR 4 — (wherein the same meaning as the R 4 wavy group). Preferred examples of R 4 are hydrogen and C 1-4 alkyl.
When Z is a bond, the fused ring of formula (I) is preferably an imidazopyridine ring.
Provided that ring A is a 5-membered ring of formula A ′ (wherein X is carbon and X 1 is sulfur), W is a bond, Z is —NHCO— or —CONH—, Compounds where Y 1 is CR 3a (wherein R 3a is hydrogen, halogen, or alkoxy) are excluded from compounds of formulas (I) and (Ia), and ring A is 5 of formula A ′. A membered ring (wherein X is carbon, X 1 is oxygen, sulfur or —NH—), R 1 is optionally substituted 1-piperazinyl, W is a bond, Z Compounds wherein is a bond and R 2 is optionally substituted aryl are excluded from the compounds of formula (I).
Preferred compounds of formula (I) and (Ia) include Y 1 as CR 3a , Y 2 as CR 3b , Y 3 as CR 3c (wherein R 3a , R 3b and R 3c are independently hydrogen, halogen Or an optionally substituted hydrocarbyl); W is a bond; R 2 is an optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocycle; and Z is — NR 4 - (wherein, R 4 is hydrogen or a hydrocarbyl substituted) compound is are exemplified.

  Compound (I) or (Ia) may be in the form of a prodrug thereof. A prodrug of compound (I) or (Ia) is a compound that is converted to compound (I) or (Ia) by reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, (i) enzymatically oxidized, It refers to a compound that undergoes reduction, hydrolysis, etc. and changes to compound (I) or (Ia), (ii) a compound that undergoes hydrolysis, etc., by gastric acid, etc., and changes to compound (I) or (Ia). As the prodrug of the compound (I) or (Ia) to be used, a compound or a salt thereof in which the hydroxyl group of the compound (I) or (Ia) is acylated, alkylated, phosphorylated or borated (eg, compound (I ) Or (Ia) wherein the hydroxyl group is converted to acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, dimethylaminomethylcarbonyloxy or the like), compound (I) or ( A compound in which the carboxyl group of Ia) is esterified or amidated or a salt thereof (eg, the carboxyl group of compound (I) or (Ia) is ethyl esterified, phenyl esterified, carboxyoxymethyl esterified, dimethylaminomethyl ester Pivaloyl oxime Esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolan-4-yl) methyl esterified, cyclohexyloxycarbonyl esterified or methylamidated compound, etc. ) And the like. These prodrugs can be produced by a method known per se or a modification thereof.

  In addition, prodrugs of compound (I) or (Ia) can be obtained by subjecting compound (I) or (Ia) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, pages 163 to 198. It may be a compound to be converted into (Ia) or a salt thereof.

General Synthesis Method Hereinafter, the production of the compound of formula (I) or a salt thereof according to the present invention will be described. The following examples are intended to illustrate the invention and those skilled in the art can use other methods.
Production methods of compound (I) or a salt thereof of the present invention are shown in the following methods A to E.
(Method A)
Scheme 1
Wherein R 1a and R 1b are independently substituted hydrocarbyl groups, or R 1a and R 1b may be in the form of an optionally substituted ring, R 1aa , R 1bb, R 1 cc and R 1dd are independently hydrogen or optionally substituted hydrocarbyl group, or, R 1aa and R 1bb or R 1 cc and R 1dd are good ring optionally substituted L 1 may be a leaving group (eg, halogens such as chlorine, bromine and iodine, sulfonyloxy groups such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, acetyloxy And other symbols have the same meanings as described above).

In step A, compound (III) or a salt thereof can be synthesized by hydrogenating compound (II) or a salt thereof in the presence of a catalytic reduction catalyst or by a reduction reaction of compound (II) or a salt thereof.
Catalysts include palladium catalysts such as palladium black, palladium oxide, palladium barium sulfate, palladium carbon and palladium hydroxide, platinum catalysts such as platinum black, platinum oxide and platinum carbon, or nickel catalysts such as reduced nickel, nickel oxide and Raney nickel. Is used.
In this reaction, any solvent can be used if necessary as long as the reaction is not inhibited. Among them, alcohols (eg, C 1-3 alcohols such as methanol, ethanol, propanol), ethers (eg, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane etc.), or esters (eg, acetic acid) Ethyl etc.) are preferred. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature is 0 ° C to 200 ° C, preferably 20 ° C to 100 ° C. The reaction time is usually 0.5 to 48 hours, preferably 1 to 16 hours. The reaction is usually carried out at atmospheric pressure, but may be carried out under pressure (3 to 10 atm) if necessary.
The amount of catalyst used varies depending on the type of catalyst used, but is usually 0.1 to 20% by weight based on the active intermediate or its salt.

Compound (III) or a salt thereof can also be produced by reduction of compound (II) or a salt thereof. The reducing agent is preferably iron, zinc or tin stannous chloride.
This reaction may be performed under acidic conditions. Examples of the acid used in this reduction reaction include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, ordinary organic acids such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, and Lewis acids.
Examples of the reaction solvent include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, and halogenation such as chloroform and dichloromethane. Examples thereof include hydrocarbons, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
Although reaction temperature changes with substrates used with other conditions, it is -20-200 degreeC, Preferably it is 0-100 degreeC. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 10 hours.
Compound (II) or (III) or a salt thereof can be produced by Schemes 2-9.
The compound (II) or (III) thus obtained can be isolated and purified by known isolation / purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. Can be purified.

In Step B-1, compound (Ia) or a salt thereof contained in the compounds (I) of the present invention, compound (III) or a salt thereof and the carbonyl compound R 1aa R 1bb C = O or R 1cc R 1dd C = O The imine can be produced in situ and then catalytically reduced in the presence of a suitable reducing agent or catalytic reduction catalyst.
When R 1a and R 1b in the compound (Ia) are the same, R 1aa R 1bb C═O can be used in Step B-1. When in the compound (Ia) R 1a is not the same as R 1b, step in Step B-1 to Gyouru alkylation reaction using R 1aa R 1bb C = O and R 1cc R 1dd C = O.
The reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanotrihydroborate and sodium triacetoxyhydroborate.
The catalytic reduction catalyst is preferably palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium carbon, palladium hydroxide, platinum catalyst such as platinum black, platinum oxide and platinum carbon, or reduced nickel, nickel oxide, Raney nickel. Nickel catalysts such as are used. In this reaction the compound (III) or a salt thereof to 1 mole, the carbonyl compound R 1aa R 1bb C = O, R 1cc R 1dd C = O 1~10 moles, preferably 1 to 3 mol, and a reducing agent 0 .5 to 10 mol, preferably 0.5 to 3 mol is used. Examples of the reaction solvent include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, and halogenation such as chloroform and dichloromethane. Hydrocarbons, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like are used. These solvents may be used by mixing at an appropriate ratio.

When producing imines, the use of molecular sieves or the addition of acidity accelerates the reaction. The acid used here is preferably acetic acid or trifluoroacetic acid. Although the reaction temperature in this imine production changes with compound (III) or its salt with other conditions, it is 0-200 degreeC, Preferably it is 0-150 degreeC. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
The reaction temperature in the reduction reaction is -20 to 200 ° C, preferably 0 to 100 ° C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 12 hours.

Compound (Ia) or a salt thereof can also be produced by reacting compound (III) with R 1a L 1 or R 1b L 1 . When R 1a and R 1b in Compound (Ia) are the same, R 1a L 1 can be used in Step B-2. When R 1a is not the same as R 1b in the compound (Ia), an alkylation reaction can be performed using R 1a L 1 and R 1b L 1 stepwise in Step B-2.
In Step B-2, the compound represented by R 1a L 1 or a salt thereof is 1 to 10 mol, preferably 1 to 5 mol, and a base 1 to 10 mol, relative to 1 mol of the compound (III) or a salt thereof. Preferably 1 to 3 moles are used.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is used.

Solvents that do not adversely affect the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform and dichloromethane Halogenated hydrocarbons, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (III) or a salt thereof used together with other conditions, it is -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
Alkylation of compound (III) for preparing compound (Ia) can be carried out by a combined reaction of steps B-1 and B-2.
The compound (Ia) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 2
(Wherein Z 1 is oxygen, sulfur, —NR 4 —, or —NR 4 —alk—, Z 1a is —SO— or —SO 2 —, and W 2 is NO 2 or NH 2 . , L 1 is a leaving group (eg, halogen such as chlorine, bromine and iodine, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, acetyloxy group and benzoyloxy group) And other symbols have the same meanings as above.)

Compound (IIa) or a salt thereof contained in compound (II) or (III) can be prepared by reacting compound (IV) with R 2 Z 1 H. Compound (IV) or a salt thereof can be produced by the following scheme 10 or 11.
In Step C-1, 1 to 5 mol, preferably 1 to 3 mol, and 1 to 5 mol of a base represented by R 2 Z 1 H or a salt thereof, relative to 1 mol of compound (IV) or a salt thereof 1 to 3 moles are preferably used.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is used.

Solvents that do not adversely affect the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform and dichloromethane Halogenated hydrocarbons, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (IV) or the salt thereof used together with other reaction conditions, it is -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
In R 2 Z 1 H, when Z 1 is —NR 4 — or —NR 4 -alk—, compound (IIa) or a salt thereof contained in compound (II) or (III) is compound (IV). In the presence of R 2 Z 1 H or a salt thereof and a palladium catalyst, preferably palladium (II) acetate and a catalytic amount of a phosphine ligand, preferably 2- (dicyclohexylphosphino) biphenyl, Buchwald et al. (J. Am. Chem. Soc., 1998, 120, 9722) and a similar method.
In the compound (IIa), when Z 1 is sulfur, the compound (IIaa) or a salt thereof included in the compound (II) or (III) can be prepared by oxidizing the compound (II) or a salt thereof. .
The oxidizing agent is preferably hydrogen peroxide, an organic oxide (eg, 3-chloroperbenzoic acid, peracetic acid, etc.), manganese (IV) oxide, or sodium metaperiodate.

In Step C-2, 1 to 10 mol, preferably 1 to 5 mol of an oxidizing agent is used per 1 mol of compound (IIa) or a salt thereof.
This reaction may be performed under acidic conditions. Examples of the acid used in this oxidation reaction include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, ordinary organic acids such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, and Lewis acids.
Examples of the reaction solvent include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform and dichloromethane. Halogenated hydrocarbons, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like are used. These solvents may be used by mixing at an appropriate ratio.
Although reaction temperature changes with substrates used with other conditions, it is -20-200 degreeC, Preferably it is 0-100 degreeC. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 10 hours. The compounds (IIa) and (IIaa) thus obtained are isolated and purified by known isolation / purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. Can be purified.

Scheme 3
(In the formula, Z2 is a bond, and other symbols have the same meanings as described above.)

Compound (IIb) or a salt thereof contained in compound (II) or (III) is obtained by converting compound (IV) into boronic acid R 2 B (OH) 2 or a boronic acid ester or a salt thereof, a palladium catalyst, preferably tetrakis ( It can be prepared according to the method of Suzuki coupling (Organic Synthesis via Boranes, vol. 3: Suzuki coupling, A. Suzuki and HC Brown, Aldrich, 2002) in the presence of triphenylphosphine) palladium (0) and a base. Compound (IV) or a salt thereof can be prepared by the following scheme 10 or 11.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is used.

Examples of the solvent that does not adversely influence the reaction include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, Halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (IV) or its salt used together with other reaction conditions, it is -20 to 200 ° C, preferably 40 to 150 ° C. The reaction time is 5 minutes to 48 hours, preferably 1 hour to 24 hours.
The compound (IIb) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 4
(In the formula, Z 3 is C═O, and the other symbols have the same meanings as described above.)
Compound (IIc) or a salt thereof contained in compound (II) or (III) is prepared by reacting compound (IV) with acid chloride R 2 COCl or a salt thereof, and then treating with an organometallic reagent. Can do. Compound (IV) or a salt thereof can be prepared by the following scheme 10 or 11.
In Step E, the organometallic reagent is used in an amount of 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of compound (IV) or a salt thereof. The organometallic reagent is preferably organolithium such as n-butyllithium, sec-butyllithium, tert-butyllithium.

Examples of the solvent that does not adversely influence the reaction include ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide. And sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature varies depending on the reagent used together with other reaction conditions, but is −100 to 200 ° C., preferably −78 to 100 ° C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 10 hours.
The compound (IIc) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 5
(Wherein, R 4a and R 4b are each independently an optionally substituted hydrocarbyl, L 2 is a leaving group, and each symbol has the same meaning as described above.)
In Step F-1, compound (VI) or a salt thereof is produced from compound (V) or a salt thereof and aldehyde compound R 4 CHO without immobilization, and subsequently, there is an appropriate reducing agent or catalytic reduction catalyst. It can be produced by catalytic reduction below. The reaction can be carried out in the same manner as in Step B of Scheme 1 to prepare compound (VI). Compound (V) or a salt thereof can be prepared according to Scheme 10 below.
In Step F-2, compound (VI) or a salt thereof can be prepared by reacting (V) with R 4 L 2 or a salt thereof.
This reaction is carried out in the presence of a base according to a conventional method in a solvent that does not adversely influence the reaction. Specific examples of the leaving group L 2 include halogens such as chlorine, bromine and iodine, sulfonyloxy groups such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, acetyloxy group and benzoyloxy group. And acyloxy groups.

Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] unde. Amines such as -7-cene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide.
The amount of these bases used is preferably about 1 to about 5 equivalents relative to compound (V).

Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; N, N-dimethylformamide And sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature is generally about −50 to about 150 ° C., preferably −10 to 120 ° C. The reaction time is usually 0.5 to 20 hours.
The compound (VI) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

In Step G, compound (IId), the reactive inductive element compound of a carboxylic acid R 2 COOH or a carboxyl group (VI) or other Ru is prepared by reacting a salt thereof.
Suitable reactive derivatives of the carboxyl group of R 2 COOH include acid halides, acid anhydrides, active amides, active esters and the like. Examples of suitable reactive derivatives are: acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thio Such as sulfuric acid, sulfuric acid, sulfonic acid such as methanesulfonic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentacarboxylic acid, isopentanoic acid, trichloroacetic acid and other aliphatic carboxylic acids or benzoic acid and other aromatic carboxylic acids Mixed acid anhydride with acid; Symmetric acid anhydride; Active amide with imidazole; 4-Substituted imidazole, dimethylpyrazole, triazole or tetrazole; Cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, trichloro Phenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl ester, p-cresylthioester, carboxylmethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc. Or N-hydroxy such as N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole Examples include esters with compounds. These reactive derivatives can optionally, Ru can be selected by the type of the compound used (VI).

When R 2 COOH is used in this reaction in the form of a free acid or salt thereof, the reaction is N, N-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N ′-(4 -Diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole) ); Pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; polyethyl phosphate; polyisopropyl phosphate; Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5 hydroxide -(M-sulfophenyl) isoxazolium inner salt; N-hydroxybenzotriazole; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N-dimethylformamide and thionyl chloride It is desirable to carry out the reaction in the presence of a commonly used condensing agent such as a so-called Vilsmeier reagent prepared by reaction with phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like. The reaction is carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine. May be. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or warming.

The amount of R 2 COOH to be used is 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (VI).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
When mixed acid anhydride is used, R 2 COOH and chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) are used as a base (eg, triethylamine, N-methylmorpholine, N, N-dimethyl). Reaction in the presence of aniline, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) and further with compound (VI).
The amount of R 2 COOH to be used is 1 to 10 mol, preferably 1 to 3 mol, relative to compound (VI).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
The compound (IId) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 6
(In the formula, each symbol has the same meaning as above.)
Step H is performed in the same manner as in Step G of Scheme 5 to prepare compound (IIe) or a salt thereof contained in compound (II) or (III). Compound (VII) or a salt thereof can be prepared according to Scheme 12 below.

Scheme 7
(In the formula, each symbol has the same meaning as above.)
Compound (IIf) or a salt thereof contained in compound (II) or (III) can be prepared by treating compound (VIIIa) or a salt thereof with a halogenating agent. Compound (VIIIa) or a salt thereof can be prepared by the following scheme 13 or 14.
Examples of the halogenating agent include chlorine, bromine, iodine, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and the like.
In Step I, the halogenating agent is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, relative to 1 mol of compound (VIIIa) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform and dichloromethane And the like, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like are used. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature varies depending on the reagents used together with other conditions, but is -20 to 200 ° C, preferably 20 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
The compound (IIf) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 8
(In the formula, each symbol has the same meaning as above.)
Compound (IIg) or a salt thereof contained in compound (II) or (III) can be prepared by treating compound (VIIIb) with a desulfurizing agent. Compound (VIIIb) or a salt thereof can be prepared by the following scheme 13 or 14.
Examples of the desulfurizing agent include N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4-diethylaminocyclohexyl) carbodiimide, N, N′-diethylcarbodiimide. N, N′-diisopropylcarbodiimide, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide, mercury (II) chloride, mercury (II) oxide, copper bromide (II), copper (II) chloride, Examples thereof include silver oxide, silver (I) oxide and silver carbonate.

In Step J, the dehydrosulfurizing agent is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (VIIIb) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform and dichloromethane And the like, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like are used. These solvents may be used by mixing at an appropriate ratio.
The reaction is carried out using an alkali metal salt such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] unde-7- Amines such as cene; metal hydrides such as potassium hydride and sodium hydride; and in the presence of inorganic bases and organic bases such as alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. Good.
The reaction temperature varies depending on the reagent used together with other conditions, but is -20 to 150 ° C, preferably 20 to 100 ° C. The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours.
The compound (IIg) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 9
(In the formula, each symbol has the same meaning as above.)
Compound (IIh) or a salt thereof contained in compound (II) or (III) can be prepared by treating compound (VIIIc) with a dehydrosulfurizing agent. Compound (VIIIc) or a salt thereof can be prepared according to Scheme 13 or 14 below.
Step K is carried out in the same manner as Step J in Scheme 8 to prepare compound (IIh).

Scheme 10
(Wherein X 2 is H, OH or NHR 5 , L 3 is a halogen such as chlorine, bromine and iodine, and the other symbols have the same meanings as described above.)
In Step L, compound (X) or a salt thereof is prepared by treating compound (IX) with ammonia. Compound (IX) or a salt thereof is mainly commercially available, or can be produced by reacting thiophosgene with amino derivative (XIV) as described below (Scheme 13).
Examples of the solvent include ethers such as water, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, acetonitrile and the like. Examples include nitriles, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature varies depending on the reagents used together with other conditions, but is -20 to 200 ° C, preferably 20 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
The compound (IIg) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Step M is carried out according to steps I, J or K of Schemes 7-9 to prepare compound (V).
In Step N, the amino group of compound (V) is converted to a diazonium salt, and a halogenating agent is reacted with it according to the method of Sandmeyer reaction to prepare compound (IVa) contained in compound (IV). The diazotization in this method is carried out in the presence of an acid according to a conventional method in a solvent that does not adversely influence the reaction. As the acid, for example, acetic acid and hydrochloric acid are used. As the diazotizing agent, sodium nitrite, alkyl nitrite or sulfated nitrosyl is used.
The diazonium salt of compound (V) thus obtained is reacted with a halogenating agent to produce compound (IV). Examples of the halogenating agent include chlorine, bromine, iodine, copper (I) bromide, copper (II) bromide, copper (I) chloride, copper (II) chloride and the like.
Examples of the solvent include ethers such as water, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, acetonitrile and the like. Examples include nitriles, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature is generally about −50 ° C. to about 150 ° C., preferably about −10 to about 100 ° C. The reaction time is usually about 0.5 to about 20 hours.
The compound (IVa) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 11
(In the formula, X 3 is SH, OH or NHR 5 , and the other symbols have the same meanings as described above.)
In step O, compound (XII) or a salt thereof is obtained by converting compound (IX) with 1,1′-carbonyldiimidazole, phosgene, alkyl haloformate such as ethyl chloroformate, phenyl haloformate such as phenyl chloroformate, urea or the like. It can be manufactured by processing. Compound (XI) or a salt thereof is mainly commercially available, or can be prepared from a nitro derivative corresponding to compound (XI).
Examples of the solvent include ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, and nitriles such as acetonitrile. , N, N-dimethylformamide, amides such as N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature varies depending on the reagents used together with other conditions, but is -20 to 200 ° C, preferably 20 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
The compound (XII) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

In Step P, after the base treatment of compound (XII), the resulting residue may be converted to a leaving group to produce compound (IV).
Such leaving groups include, for example, substituted sulfonyloxy (such as methanesulfonyloxy and p-toluenesulfonyloxy), acyloxy (such as acetoxy and benzoyloxy) and heterocyclic or aryl groups (succinimide, An oxy group substituted with benzotriazole, quinoline, 4-nitrophenol and the like).
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is used.
In step P, compound (IV) or a salt thereof can also be prepared by treating compound (XII) with a halogenating agent.
Examples of the halogenating agent include chlorine, bromine, iodine, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and the like.
The halogenating agent is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (XII) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform and dichloromethane And the like, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like are used. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature varies depending on the reagents used together with other conditions, but is -20 to 200 ° C, preferably 20 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
The compound (IV) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 12
(In the formula, each symbol has the same meaning as above.)
In step Q, the amino group of compound (V) is converted to a diazonium salt according to the method of Sandmeyer reaction, and a cyanating agent is reacted with it to prepare compound (XIII). The diazotization of this process is carried out in the presence of an acid in a solvent that does not adversely influence the reaction according to a conventional method. As the acid, for example, acetic acid, sulfuric acid and hydrochloric acid are used. As the diazotizing agent, sodium nitrite, alkyl nitrite or sulfated nitrosyl is used.
The diazonium salt of compound (V) thus obtained is reacted with a cyanating agent to prepare compound (XIII).
Examples of the cyanating agent include copper cyanide, potassium cyanide, sodium cyanide, nickel cyanide and the like.
Examples of the solvent include ethers such as water, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, acetonitrile and the like. Examples include nitriles, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature is generally about −50 to about 150 ° C., preferably about −10 to about 100 ° C. The reaction time is usually about 0.5 to about 20 hours.
The compound (XIII) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

In Step R, compound (VII) or a salt thereof can be prepared from compound (XIII) or a salt thereof by hydrolysis.
Hydrolysis is preferably performed in the presence of a base or acid. Examples of the acid to be used include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid. Examples of the base include inorganic bases (alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydrogen carbonate, hydrogen carbonate). Alkali metal bicarbonates such as potassium, and alkali metal carbonates such as sodium carbonate and potassium carbonate).
This reaction is carried out with 20 to 50 volumes of the aqueous inorganic acid solution per 1 g of nitrile compound (XIII) (usually 10 to 30%) or with an aqueous solution containing 3 to 10 moles of the base per mole of nitrile compound (XIII). In consideration of the solubility of the compound, the reaction may be performed in the above aqueous solution supplemented with an organic solvent. Examples of the organic solvent used include alcohols such as methanol and ethanol, organic acids such as acetic acid, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like. Examples include amides and sulfoxides such as dimethyl sulfoxide.
Although reaction temperature changes with nitriles used with other conditions, it is 0-200 degreeC, Preferably it is 20-150 degreeC. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.
The compound (VII) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 13
(In the formula, each symbol has the same meaning as above.)
Compound (VIII) or a salt thereof can be prepared by reacting (XIV) with R 2 NCS or a salt thereof.
In Step S, isothiocyanate R 2 NCS is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (XIV) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform, Halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
Although reaction temperature changes with compounds (XIV) used with other reaction conditions, it is 0-200 degreeC, Preferably it is 20-150 degreeC. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
The compound (VIII) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 14
(In the formula, each symbol has the same meaning as above.)
Compound (VIII) or a salt thereof can also be prepared by reacting (IX) with R 2 NH 2 or a salt thereof.
In step T, compound R 2 NH 2 is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (IX) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform, Halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
Although reaction temperature changes with compounds (IX) used with other reaction conditions, it is 0-200 degreeC, Preferably it is 20-150 degreeC. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
The compound (VIII) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

(Method B)
Scheme 15
(In the formula, each symbol has the same meaning as above.)
Step U is performed in the same manner as in Steps C, D, and E of Schemes 2 to 4, to prepare compound (Ib) contained in compound (I). Compound (XV) or a salt thereof can be prepared according to Scheme 16 below.

Scheme 16
(In the formula, each symbol has the same meaning as above.)
Compound (XVIII) or a salt thereof can be prepared by reacting compound (XVI) with compound (XVII).
In Step V, 1 to 5 mol, preferably 1 to 3 mol, of compound (XVII) or a salt thereof is used relative to 1 mol of compound (XVI) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform, Halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
This reaction may be performed under basic conditions. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is used.
While the reaction temperature varies depending on the compound (XVII) or a salt thereof used together with other reaction conditions, it is -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained compound (XVIII) can be isolated and purified by known isolation and purification methods, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Step W is performed in the same manner as in Steps B-1 and B-2 of Scheme 1 to prepare compound (XIX).
In step X, compound (XV) or a salt thereof can be prepared by reacting compound (XIX) with a halogenating agent.
Examples of the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, chlorine, bromine, iodine, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride. Etc.
In Step X, the halogenating agent is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (XIX) or a salt thereof.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform, Halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
The reaction temperature varies depending on the reagents used together with other conditions, but is -50 to 200 ° C, preferably 0 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
The compound (XV) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

(Method C)
Scheme 17
(In the formula, each symbol has the same meaning as above.)
Compound (Ic) or a salt thereof contained in compound (I) can be prepared by reacting compound (XX) with amino compound R 1a R 1b NH. Compound (XX) or a salt thereof can be prepared by the methods described in Methods A and B.
In Step Y, 1 to 5 mol, preferably 1 to 3 mol, and 1 to 5 mol, preferably 1 to 3 mol of the compound represented by R 1a R 1b NH are added to 1 mol of compound (XX) or a salt thereof. Used against.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is used.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform, Halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (XX) or a salt thereof used together with other reaction conditions, it is -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.

When n is 0 in compound (XX), compound (Ic) converts compound (XX) into R 1a R 1b NH or a salt thereof and a palladium catalyst, preferably palladium (II) acetate and a catalytic amount of a phosphine ligand, preferably 2 It can also be produced by reacting according to the method of Buchwald et al. (J. Am. Chem. Soc., 1998, 120, 9722) and similar methods in the presence of (dicyclohexylphosphino) biphenyl.
The compound (XV) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

(Method D)
Scheme 18
(Wherein R 3 is an optionally substituted carbon atom, and each symbol has the same meaning as described above.)
In Step Z, compound (XXII) is prepared by removing the carboxyl protecting group. Compound (XXI) or a salt thereof can be prepared by methods A, B, E and the method described in Scheme 19.
Any conventional means used for the removal reaction of the carboxyl protecting group, for example, hydrolysis, reduction and elimination reaction using Lewis acid can be used for this reaction. Hydrolysis is preferably performed in the presence of a base or acid. Suitable bases include, for example, alkali metal hydroxides (eg, sodium hydroxide and potassium hydroxide) alkaline earth metal hydroxides (eg, magnesium hydroxide and calcium hydroxide), alkali metal carbonates (eg, Sodium carbonate and potassium carbonate), alkaline earth metal carbonates (eg, magnesium carbonate and calcium carbonate), alkali metal bicarbonates (eg, sodium bicarbonate and potassium bicarbonate), alkali metal acetates (eg, sodium acetate and Inorganic bases such as potassium acetate), alkaline earth metal phosphates (eg, magnesium phosphate and calcium phosphate) and alkali metal hydrogen phosphates (eg, disodium hydrogen phosphate and dipotassium hydrogen phosphate), trialkyl Amines (eg, trimethylamine and triethylamine), Choline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.2] non-5-ene, 1,4-diazabicyclo [2.2.2] non-5-ene and 1, And organic bases such as 8-diazabicyclo [4.3.0] -7-undecene. Hydrolysis using a base is often performed in water, a hydrophilic organic solvent or a mixed solvent. Suitable acids include formic acid, hydrochloric acid, hydrobromic acid and sulfuric acid.
This hydrolysis reaction is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not particularly limited, but is appropriately selected depending on the carboxyl protecting group and the type of elimination reaction. In the elimination reaction using a Lewis acid, the compound (XXI) or a salt thereof is converted into a Lewis acid such as boron trihalide (eg, boron trichloride and boron trifluoride), titanium tetrahalide (eg, titanium tetrachloride and Titanium tetrabromide), and reaction with aluminum halides (eg, aluminum chloride and bromide) or organic acids (eg, trichloroacetic acid and trifluoroacetic acid). This elimination reaction is preferably performed in the presence of a cation scavenger (eg, anisole and phenol) and is usually nitroalkane (eg, nitromethane and nitroethane), alkylene halide (eg, methylene chloride and ethylene chloride), diethyl ether , Carbon disulfide, and solvents that do not adversely affect the reaction. These solvents may be used by mixing them.
The elimination reaction by reduction is preferably applied to elimination of protecting groups such as alkyl halides (eg, 2-iodoethyl and 2,2,2-trichloroethyl) esters and aralkyl (eg, benzyl) esters. Reduction methods used in this elimination reaction include, for example, metals (eg, zinc and zinc amalgam) or salts of chromium compounds (eg, chromium chloride and chromium acetate) and organic or inorganic acids (eg, acetic acid, propionic acid and hydrochloric acid). Or a conventional catalytic reduction in the presence of a conventional metal catalyst (eg, palladium on carbon and Raney nickel). The reaction temperature is not particularly limited, but the reaction is carried out under cooling, at room temperature or under heating.
The compound (XXII) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.
In step AA, compound (Id) or a salt thereof included in compound (I) is converted into compound (XXII) or a reactive derivative of its carboxyl group and its salt as amino compound R 1a R 1b NH or its amino group. Prepared by reacting with a derivative or salt thereof.
Step AA can be performed in the same manner as in Step G of Scheme 5 to prepare compound (Id) contained in compound (I).

Scheme 19
(In the formula, each symbol has the same meaning as above.)
Step AB can be performed in the same manner as in Step T of Scheme 14 to prepare compound (XXIV) or a salt thereof. Compound (XXIII) or a salt thereof can be prepared from an amino derivative corresponding to compound (XXIII).
Step AC can be performed in the same manner as in Step I of Scheme 7 to prepare compound (XXIa) or a salt thereof included in compound (XXI).

(Method E)
Scheme 20
(In the formula, each symbol has the same meaning as above.))
Step AD can be performed in the same manner as in Steps C, D, and E of Schemes 2 to 4, and compound (Ie) contained in compound (I) can be prepared. Compound (XXV) or a salt thereof can be prepared by the methods described in Methods A and B and Scheme 21.

Scheme 21
(In the formula, each symbol has the same meaning as above.)
Step AE can be performed in the same manner as in Step P of Scheme 11 to prepare compound (XXVa) contained in compound (XXV). Compound (XXVI) or a salt thereof can be prepared by the method described in the following scheme 22-25.

Scheme 22
(In the formula, each symbol has the same meaning as above.)
Step AF can be performed in the same manner as in Step A of Scheme 1 to prepare compound (XXVIII) or a salt thereof. Compound (XXVII) or a salt thereof can be prepared by the method described in Step O of Scheme 11.
Step AG can be performed in the same manner as in Step B of Scheme 1 to prepare compound (XXVIa) or a salt thereof included in compound (XXVI).

Scheme 23
(In the formula, R 1e is an optionally substituted aryl or an optionally substituted heteroaryl, and other symbols have the same meanings as described above.)
Compound (XXVIb) or a salt thereof included in Compound (XXVI) is obtained by reacting Compound (XXVIII) with R 1aa R 1bb ═O, R 1a L 1 in the same manner as in the method described in Steps B-1 and B-2 of Scheme 1. Or reacted with a salt thereof and then according to the method of Buchwald coupling (Topics in Current Chemistry, 219, 131-209 (2002)) in the presence of R 1e L 1 or a salt thereof and a palladium catalyst, a phosphine ligand, and a base. Compound (XXVIb) is prepared by reaction. The order of these two steps AH-1 and AH-2 may be changed. Compound (XXVIII) or a salt thereof can be prepared according to Scheme 22 below.
In step AH-2, examples of the palladium catalyst include bis (triphenylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), and trans-dichlorobis (tri-o-tolylphosphine) palladium. , Palladium (II) trifluoroacetate and palladium (II) acetate, preferably tris (dibenzylideneacetone) dipalladium (0). Examples of the phosphine ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2- (Dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1,1′-biphenyl, 2- (dicyclohexylphosphino) -2 ′-(N, N-dimethylamino) biphenyl, 1,1′-bis (diphenyl) Phosphino) ferrocene, tri-tert-butylphosphine and tricyclohexylphosphine are preferably 2- (dicyclohexylphosphino) biphenyl and 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1,1′-biphenyl Is mentioned. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate. Cesium salts such as, alkali metal hydrides such as sodium hydride, potassium hydride, sodium amide, sodium methoxide, sodium ethoxide, alkoxides such as sodium tert-butoxide and potassium tert-butoxide, trimethylamine, triethylamine and diisopropylethylamine And cyclic amines such as pyridine.
In step AH-2, R 1e L 1 1.0 to 5 mol, preferably 1.1 to 2.0 mol, palladium catalyst 0.01 to 0.5 mol, relative to 1 mol of the amino compound or a salt thereof, Preferably 0.05 to 0.2 mol, phosphine ligand 0.01 to 0.5 mol, preferably 0.02 to 0.2 mol and base 1.0 to 5.0 mol, preferably 1.2 to 3 Use moles.
Examples of the solvent that does not adversely influence the reaction include ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as chloroform and dichloromethane. Nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (XIIa) or a salt thereof used together with other reaction conditions, it is 0 to 250 ° C, preferably 50 to 150 ° C. The reaction time is 5 minutes to 120 hours, preferably 1 to 48 hours.

As another route, compound (XXVIb) or a salt thereof can be prepared via compound (XXIX).
In step AI, compound (XXIX) can be prepared in a manner similar to that described in Step N of Scheme 10 or by reacting compound (XXVIII) with an alkyl nitrite and a metal halide.
In step AI, methyl nitrite is used in an amount of 1.0 to 5 mol, preferably 1.0 to 2.0 mol, and metal halide is used in an amount of 0.5 to 3 mol, preferably 0.5 to 2 mol.
Examples of the solvent that does not adversely influence the reaction include ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as chloroform and dichloromethane. Nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (XXVIII) or a salt thereof used together with other reaction conditions, it is −10 to 200 ° C., preferably 0 to 100 ° C. The reaction time is 5 minutes to 120 hours, preferably 30 minutes to 24 hours.
The thus obtained compound (XXIX) can be isolated and purified by known isolation and purification methods, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Step AJ is carried out in the same manner as in Step AH-2, and compound (XXX) can be prepared by reacting with R 1e NH 2 or a salt thereof.
Step AK can be performed in the same manner as in Step B of Scheme 1 to prepare compound (XXVIb).
The thus obtained compound (XXVIb) can be isolated and purified by known isolation and purification methods, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 24
(In the formula, R 1f is an optionally substituted alkyl, an optionally substituted carboxyl or an optionally substituted carboxyamide, and other symbols have the same meaning as described above.)
Compound (XXVIc) or a salt thereof included in compound (XXVI) can be prepared by oxidation of cycloalkene and subsequent reductive alkylation of compound (XXVIII). Compound (XXVIII) or a salt thereof can be prepared according to Scheme 22 above.
In the oxidation step, an oxidizing agent is used, and a base or an acid may be used.
Examples of the oxidizing agent include potassium permanganate, potassium periodate, sodium periodate, sodium dichromate, potassium dichromate, osmium tetroxide, ruthenium tetroxide, oxygen, ozone, hydrogen peroxide, 3- Organic peroxides such as chloroperbenzoic acid and peracetic acid, preferably ozone. These reagents may be used by mixing at an appropriate ratio.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, cesium carbonate Cesium salts such as, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as pyridine, etc. Is mentioned.
Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, and usual organic acids such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, and Lewis acids.
In the oxidation reaction, 1 to 10 moles, preferably 1 to 3 moles, 0.1 to 10 moles, preferably 0.3 to 2 moles of base are used per 1 mole of compound (XXVIII) or a salt thereof. It is done.
Examples of solvents that do not adversely influence the reaction include alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, Halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature varies depending on the compound (XXVIII) or a salt thereof used together with other reaction conditions, it is −100 to 200 ° C., preferably −100 to 100 ° C. The reaction time is 1 minute to 48 hours, preferably 1 minute to 24 hours.
The oxide thus obtained can be isolated and purified by known isolation / purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography.
In the reductive alkylation step, the method described in scheme B, step B-1 is used. The thus obtained compound (XXVIc) can be isolated and purified by known isolation and purification methods, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution and chromatography. it can.

Scheme 25
Step AM can be performed in the same manner as in Step O of Scheme 11 to prepare compound (XXVId) or a salt thereof. Compound (XXXI) or a salt thereof can be prepared from a nitro derivative corresponding to compound (XXXI).

Compound (I) obtained as a free form by any of the above methods is prepared according to standard techniques, for example, by using an inorganic acid (for example, hydrochloric acid, sulfuric acid and hydrobromic acid), an organic acid (for example, methanesulfone). Acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum and ammonium, etc.) ) Or organic bases (eg trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N′-dibenzylethylenediamine etc.), while compounds (I) as salt If obtained, it can be converted to the free form or other salts according to standard techniques.
The thus obtained compound (I) or a salt thereof can be purified and recovered using a separation / purification method known per se (for example, concentration, solvent extraction, column chromatography, recrystallization and the like).
The starting material of the compound (I) of the present invention includes salts with inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid), organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid) Salt forms including salts with acids, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid and the like). When any of these compounds has an acidic group such as —COOH, a salt with an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium and magnesium, ammonia, etc.), or organic A salt with a base (for example, a tri-C 1-3 alkylamine such as triethylamine) may be formed.

In each of the above reactions, when the starting material has an amino group, amide group, urea group, carboxyl group or hydroxyl group as a substituent, such a group may be derivatized with a protective group used in ordinary peptide chemistry. If necessary, it can be decomposed to give the target compound after the reaction.
Examples of the protecting group for amino group, amide group and urea group include optionally substituted C 1-6 alkylcarbonyl (eg, formyl, methylcarbonyl and ethylcarbonyl), phenylcarbonyl, C 1-6 alkoxycarbonyl. (Eg methoxycarbonyl, ethoxycarbonyl and tert-butylcarbonyl etc.), phenyloxycarbonyl (eg benzoylcarbonyl), C 7-10 aralkylcarbonyl (eg benzyloxycarbonyl), C 7-10 aralkyl (eg benzyl and 4-methoxybenzyl etc.), trityl, phthaloyl and the like. Substituents for the above groups are halogen atoms (for example, fluorine, chlorine, bromine and iodine), C 1-6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro groups. There may be 1 to about 3 of these.
Examples of the protecting group for the carboxyl group include optionally substituted C 1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, etc.), phenyl, trityl, and the like. Examples include silyl. Substituents for the above groups are halogen atoms (eg, fluorine, chlorine, bromine and iodine), C 1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro groups. There may be 1 to about 3 of these.
Examples of the protecting group for the hydroxyl group include optionally substituted C 1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, etc.), phenyl, C 7. -10 aralkyl (eg benzyl etc.), C 1-6 alkylcarbonyl (eg formyl, methylcarbonyl and ethylcarbonyl etc.), phenyloxycarbonyl (eg benzoxycarbonyl etc.), C 7-10 aralkylcarbonyl (eg Benzyloxycarbonyl and the like), pyranyl, furanyl, silyl and the like. The substituent of each group mentioned above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine), C 1-6 alkyl, phenyl, C 7-10 aralkyl, nitro group, etc. There may be 1 to about 4.
The method for decomposing the protecting group is, for example, a method known per se such as acid, base, reduction, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetramethylammonium fluoride, palladium acetate, etc. Is the method.

  The pharmaceutical composition containing the compound (I) or (Ia) of the present invention is used for major depression, postpartum depression, inhibitory symptoms, depression, anxiety, general anxiety disorder, panic disorder, phobia, obsessive disorder, heart Post-traumatic stress disorder, Tourette syndrome, autism, emotional disorder, adaptation disorder, emotional disorder, sleep disorder, insomnia, bipolar disorder, circulatory disease, neurosis, schizophrenia, gastrointestinal ulcer, hypersensitivity Neurodegenerative diseases such as bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative bowel obstruction, stress-related gastrointestinal dysfunction and neurogenic vomiting, Alzheimer's disease, Alzheimer's senile dementia, Parkinson's disease and Huntington's disease , Cerebrovascular dementia, senile dementia, eating disorder, bulimia and other eating disorders, obesity, diabetes, alcoholism, drug preference, drug withdrawal, migraine, stress headache, tension head , Ischemic neuropathy, neuropathy, cerebral palsy, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscle spasm, chronic fatigue syndrome, glaucoma, Meniere syndrome, autonomic ataxia, alopecia , Hypertension, cardiovascular disease, tachycardia, congestive heart attack, hyperventilation, bronchial asthma, apnea, sudden infant death syndrome, inflammatory disease, pain, allergic disease, impotence, menopausal disorder, fertility disorder, Expected to be useful in the treatment and prevention of diseases involving CRF such as infertility, cancer, immune dysfunction due to HIV infection, immune dysfunction due to stress, encephalomyelitis, acromegaly, ataxia or osteoporosis The

  The compound (I) or (Ia) of the present invention is formulated with a pharmaceutically acceptable carrier to form a solid preparation such as a tablet, capsule, granule or powder; or as a liquid preparation such as a syrup or injection. It can be administered orally or parenterally. In addition, it should be made into transdermal preparations such as patches, poultices, ointments (including creams), plasters, tapes, lotions, solutions and solutions, suspensions, emulsions, sprays, etc. You can also.

As the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. For example, excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, Formulated as a solubilizer, suspension, isotonic agent, buffer, and soothing agent. If necessary, formulation additives such as preservatives, antioxidants, stabilizers, colorants, sweeteners and the like can be used.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, α-starch, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

If necessary, for the purpose of taste masking, enteric coating, or sustained action, the oral preparation may be prepared by coating by a method known per se. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], and cellulose acetate phthalate. , Hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate phthalate, Eudragit (Rohm, methacrylic acid-acrylic acid copolymer), and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose Examples thereof include hydrophilic polymer substances such as sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate, and the like. Examples of soothing agents include benzyl alcohol. Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite and ascorbic acid.

  The present invention is further illustrated in detail by the following examples and test examples, which are merely examples, and are not intended to limit the present invention and may be modified without departing from the scope of the present invention. You may let them.

N 2 -mesityl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine:
N 2 -mesityl-7-nitro-1,3-benzothiazol-2-amine:
2.25 g (12.5 mmol) of 3-nitrophenyl isothiocyanate and 1.4 mL (10 mmol) of mesitylamine were added to 10 mL of methanol and stirred at room temperature for 2 hours. The produced crystals were collected by filtration and dried to quantitatively obtain 1- (3-nitrophenyl) -3- (mesityl) thiourea. 1.8 g (5.7 mmol) of thiourea thus obtained was suspended in 20 mL of carbon tetrachloride, and 0.35 mL (6.9 mmol) of bromine was added. The reaction mixture was heated to reflux for 4 hours, cooled to room temperature and diluted with dichloromethane. The solution was washed successively with saturated aqueous sodium bicarbonate solution, water and brine and then dried over sodium sulfate. The crude product of the title compound obtained by filtering the solution and concentrating under reduced pressure was used directly without purification.
MS Calcd .: 313; Found: 314 (M + H).

N 2 -mesityl-1,3-benzothiazole-2,7-diamine:
In a solution of 1.8 g (5.7 mmol) of N 2 -mesityl-7-nitro-1,3-benzothiazol-2-amine dissolved in 7.2 mL of glacial acetic acid and 25 mL of ethanol, 1.8 g (32 mmol) of iron powder was dissolved. ) Was added. The resulting solution was heated to reflux for 18 hours and cooled to room temperature. The slurry was filtered and the filtrate was concentrated to give a brown solid. The solid was suspended in water, filtered and then purified by flash chromatography eluting with a 33% hexane / ethyl acetate mixture to give 0.9 g (55%) of the title compound as a tan powder. .
MS Calcd .: 283; Found: 284 (M + H).

N 2 -mesityl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine:
N 2 -mesityl-1,3-benzothiazole-2,7-diamine (0.125 g, 0.44 mmol) and propionaldehyde (0.16 mL, 2.2 mmol) are dissolved in dichloromethane (5 mL), and one drop of glacial acetic acid and triacetoxy are dissolved. Sodium hydroborate 0.28 g (1.3 mmol) was added. The reaction mixture was heated at 50 ° C. for 1 hour and concentrated under reduced pressure. The resulting crude solid was purified by flash chromatography eluting with a 2% methanol / dichloromethane mixture to give 0.016 g (10%) of the title compound as a tan powder.
1 H NMR (CDCl 3 ) δ 0.73 (t, J = 7.4 Hz, 6H), 1.31-1.40 (m, 4H), 2.23 (s, 6H), 2.26 (s, 3H), 2.94-2.98 (m, 4H ), 6.67 (t, J = 2.7 Hz, 1H), 6.92 (s, 2H), 7.14-7.17 (m, 2H).
MS Calcd .: 367; Found: 368 (M + H).

The compound of Example 2-6 shown in Table 1 was prepared in the same manner as Example 1. Compounds 2 and 3 were purified by reverse phase HPLC (CH 3 CN containing 0.1% TFA / water containing 0.1% TFA) to obtain a TFA salt.
Table 1

Example 7
N 2 -mesityl-N 7 , N 7 -dipropyl [1,3] thiazolo [4,5-b] pyridine-2,7-diamine:
2-chloro -N 4, N 4 - dipropyl-4-amine:
Add 0.65 g (5.1 mmol) of 4-amino-2-chloropyridine and 1.8 mL (25 mmol) of propionaldehyde to 5 mL of dichloromethane and treat with 2 drops of glacial acetic acid and 3.2 g (15 mmol) of sodium triacetoxyhydroborate. did. The reaction mixture was heated at 50 ° C. for 1 hour, and 0.9 mL (12.5 mmol) of propionaldehyde and 1.6 g (7.5 mmol) of sodium triacetoxyhydroborate were added. The reaction mixture was further heated at 50 ° C. for 36 hours. The reaction solution was cooled to room temperature and 0.15 g (4 mmol) of sodium borohydride was added. The reaction mixture was heated at 80 ° C. for 1 hour and cooled to room temperature. The reaction mixture was diluted with dichloromethane, washed successively with water and brine, and dried over sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure, and the resulting oily substance was purified by flash chromatography eluting with a 80% hexane / ethyl acetate mixture to afford 0.41 g (38%) of the title compound as a colorless oil. Obtained as material.
1 H NMR (CDCl 3 ) δ 0.91 (t, J = 7.4 Hz, 6H), 1.53-1.62 (m, 4H), 3.20 (t, J = 7.8 Hz, 4H), 6.32 (dd, J = 2.5, 6.0 Hz, 3H), 6.39 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H).

N 2 - diphenylmethylene -N 4, N 4 - dipropyl pyridine-2,4-diamine:
0.52 g (2.4 mmol) of 2-chloro-N 4 , N 4 -dipropylpyridin-4-amine, racemic 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) To a mixture of 0.076 g (0.12 mmol), sodium tert-butoxide 0.33 g (3.4 mmol) and palladium (II) acetate 0.027 g (0.12 mmol) in 25 mL of toluene was added 0.49 g of benzophenone imine. (2.9 mmol) was added and heated at 85 ° C. for 18 hours. The reaction mixture is diluted with ethyl acetate, filtered through a pad of celite and then purified by flash chromatography eluting with a 33% hexane / ethyl acetate mixture to afford 0.65 g (75%) of the title compound as a golden oil. Got as.
MS Calcd .: 357; Found: 358 (M + H).

N 4 , N 4 -dipropylpyridine-2,4-diamine:
To a solution of N 2 -diphenylmethylene-N 4 , N 4 -dipropylpyridine-2,4-diamine 0.235 g (0.66 mmol) in methanol 9 mL, sodium acetate 0.13 g (1.6 mmol) and then hydroxyamine hydrochloride 0.082 g (1.2 mmol) of salt was added. The resulting clear golden reaction mixture was stirred at room temperature for 45 minutes and then concentrated under reduced pressure. The crude product solid was suspended in dichloromethane and filtered, and the filtrate was concentrated. The resulting oily material was purified by flash chromatography eluting with a 13% -20% methanol / dichloromethane gradient containing 2% triethylamine to afford 0.106 g (83%) of the title compound as a white solid. Obtained.
MS Calcd .: 193; Found: 194 (M + H).

1- [4- (Dipropylamino) pyridin-2-yl] -3-mesitylthiourea:
0.117 g (0.66 mmol) of mesityl isothiocyanate was added to a 10 mL methanol solution of 0.106 g (0.55 mmol) of N 4 , N 4 -dipropylpyridine-2,4-diamine. The reaction mixture was heated to reflux for 24 hours, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product solid was purified by flash chromatography eluting with 85% hexane / ethyl acetate mixture to give 0.044 g (22%) of the title compound as a white solid.
MS Calcd .: 370; Found: 371 (M + H).

N 2 -mesityl-N 7 , N 7 -dipropyl [1,3] thiazolo [4,5-b] pyridin-2,7-diamine 1- [4- (dipropylamino) pyridin-2-yl] -3 -To a solution of 0.040 g (0.11 mmol) of mesitylthiourea in 2 mL of glacial acetic acid was added 6.1 μL (0.12 mmol) of bromine. After reacting at room temperature for 30 minutes, 2 μL of bromine was further added. After 2 hours, the reaction mixture was concentrated and washed with ethyl acetate / hexane. The organic layer was concentrated and the resulting oily material was purified by flash chromatography eluting with a 4% methanol / dichloromethane mixture to give 0.020 g (50%) of the title compound as a pale yellow powder.
1 H NMR (DMSO-d 6 ) δ 0.84 (t, J = 7.2 Hz, 6H), 1.50-1.56 (m, 4H), 2.17 (s, 6H), 2.27 (s, 3H), 3.30 (s, 4H ), 6.34 (d, J = 5.9 Hz, 1H), 6.98 (s, 2H), 7.88 (d, J = 5.9 Hz, 1H), 9.55 (br s, 1H).
MS Calcd .: 368; Found: 369 (M + H).

Example 8
N 2 - (1-phenylethyl) -N 7, N 7 - dipropyl-1,3-benzothiazole-2,7-diamine:
2-chloro-7-nitro-1,3 Benzochiazo le:
To a mixture of 0.195 g (1.0 mmol) 7-nitro-1,3-benzothiazol-2-amine and 0.336 g (2.5 mmol) cupric chloride in 2 mL N, N-dimethylformamide (DMF) was added. 0.15 mL (1.25 mmol) of tert-butyl nitrate was added dropwise. The reaction mixture was stirred at room temperature for 24 hours, poured into water, and the resulting crystals were collected and dried to give the title compound (0.163 g, 76%) as a tan powder.
MS Calcd .: 215; Found: 214 (MH).

7-nitro - N-(1-phenylethyl) -1,3-benzothiazol-2-Amin:
0.29 μL of racemic α-methylbenzylamine (2. 2 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with water, and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and purified by flash chromatography eluting with a 25% ethyl acetate / hexane mixture to give 0.165 g (74%) of the title compound as a pale yellow solid.

N 2 - (1-phenylethyl) -1,3-benzothiazole-2,7-diamines:
7-Nitro- N- (1-phenylethyl) -1,3-benzothiazol-2-amine 0.165 g (0.55 mmol) in DMF 10 mL solution to stannous chloride dihydrate 0.62 g (2.8 mmol) ) Was added. The reaction was heated at 80 ° C. for 48 hours and neutralized with saturated aqueous sodium bicarbonate. The reaction mixture was filtered through celite and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by flash chromatography eluting with a 50-75% ethyl acetate / hexanes gradient mixture to give 0.016 g (11%) of the title compound as a pale yellow solid.
MS Calcd .: 269; Found: 270 (M + H).

N 2 - (1-phenylethyl) -N 7, N 7 - dipropyl-1,3-benzothiazole-2,7-diamines:
1 drop of glacial acetic acid in 2 mL of dichloroethane in 0.016 g (0.059 mmol) of N 2- (1-phenylethyl) -1,3-benzothiazole-2,7-diamine and 21 μL (0.30 mmol) of propionaldehyde 0.038 g (0.18 mmol) of sodium triacetoxyhydroborate was added. The reaction mixture was heated at 50 ° C. for 3 hours and concentrated under reduced pressure. The crude product solid was purified by flash chromatography eluting with a 25% ethyl acetate / hexane mixture to give 0.008 g (38%) of the title compound as a pale golden oil.
MS Calcd .: 353; Found: 354 (M + H).

Example 9
2-morpholin-4-yl-N, N-dipropyl-1,3-benzothiazol-7-amine:

2-morpholin-4-yl-7-nitro-1,3-benzothiazole:
To a solution of 2-bromo-7-nitro-1,3-benzothiazole (0.200 g, 0.77 mmol) in DMF (2 mL) was added potassium carbonate (0.21 g, 1.5 mmol) and morpholine (81 μL, 0.93 mmol). The reaction mixture was stirred at room temperature for 72 hours and diluted with water. The resulting precipitate was collected by filtration and purified by flash chromatography eluting with a 33% ethyl acetate / hexane mixture to give 0.075 g (37%) of the title compound as a cream powder.
MS Calcd .: 265; Found: 266 (M + H).

2-morpholin-4-yl-1,3-benzothiazol-7-amine:
A small amount of Raney nickel was added to a solution of 0.075 g (0.28 mmol) of 2-morpholin-4-yl-7-nitro-1,3-benzothiazole in 6 mL of tetrahydrofuran (THF). The reaction solution was kept under a hydrogen atmosphere using a balloon and stirred at room temperature for 5 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Since it could not be purified by flash chromatography, 0.022 g (33%) of the isolated material was used without further purification.

2-morpholin-4-yl-N, N-dipropyl-1,3-benzothiazol-7-amine:
To a solution of 0.022 g (0.094 mmol) of 2-morpholin-4-yl-1,3-benzothiazol-7-amine and 40 μL (0.56 mmol) of propionaldehyde in 2 mL of dichloroethane, 1 drop of glacial acetic acid and triacetoxyhydroboric acid Sodium 0.064 g (0.30 mmol) was added. The reaction mixture was heated at 50 ° C. for 5 hours and concentrated under reduced pressure. The crude product solid was purified by flash chromatography eluting with a 17% ethyl acetate / hexane mixture to give 0.009 g (30%) of the title compound as a pale golden oil.
MS Calcd .: 319; Found: 320 (M + H).

Example 10
N- (7- (dipropylamino) -1,3-benzothiazol-2-yl) -2,4,6-trimethylbenzamide:

(3-Nitrophenyl) thiourea:
To a 25 mL methanol solution of 7.20 (40 mmol) of 3-nitrophenyl isothiocyanate, 28.5 mL (200 mmol) of a 7N ammonia methanol solution was added. After 30 minutes, the slurry was concentrated to give 7.9 g (100%) of the title compound as a yellow-orange powder without further purification.
MS Calcd .: 197; Found: 198 (M + H).

7-nitro-1,3-benzothiazol-2-amine:
To a solution of 0.60 g (3.0 mmol) of (3-nitrophenyl) thiourea in 25 mL of carbon tetrachloride, a solution of 0.17 mL (3.4 mmol) of bromine in 10 mL of carbon tetrachloride was added dropwise over 1 hour. The mixture was heated to reflux for 18 hours, cooled to room temperature, and the resulting precipitate was collected by filtration. The precipitate was suspended in glacial acetic acid, and the solid was collected by filtration. The solid thus obtained was suspended in water and saturated potassium carbonate solution was added until the pH was about 9. The free base was collected by filtration to give 0.30 g (51%) of the title compound as a pale orange solid.
MS Calcd .: 195; Found: 196 (M + H).

2,4,6-trimethyl-N- (7-nitro-1,3-benzothiazol-2-yl) benzamide 0.089 g (0.46 mmol) of 7-nitro-1,3-benzothiazol-2-amine To a 1 mL solution of pyridine, 0.17 g (0.91 mmol) of 2,4,6-trimethylbenzoyl chloride was added. The mixture was heated at 75 ° C. for 18 hours and the volatile components were removed under reduced pressure. The residue was washed with water and 1N hydrochloric acid, dissolved in ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude solid was eluted with a 25% ethyl acetate / hexane mixture by flash chromatography. To give 0.103 g (66%) of the title compound as a tan solid.
1 H NMR (DMSO-d 6 ) δ 2.21 (s, 6H), 2.26 (s, 3H), 6.95 (s, 2H), 7.72 (t, J = 8.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 12.98 (s, 1H).
MS Calcd .: 341; Found: 342 (M + H).

N- (7-amino-1,3-benzothiazol-2-yl) -2,4,6-trimethylbenzamide:
A small amount of Raney nickel was added to a solution of 2,4,6-trimethyl-N- (7-nitro-1,3-benzothiazol-2-yl) benzamide 0.200 g (0.586 mmol) in THF 5 mL. The reaction solution was kept in a hydrogen atmosphere with a balloon and stirred for 90 minutes at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a burnt orange solid. The resulting crude solid was purified by flash chromatography eluting with a 25% ethyl acetate / hexane mixture to give 0.118 g (65%) of the title compound as a pale yellow powder.
MS Calcd .: 311; Found: 312 (M + H).

N- (7-dipropylamino) -1,3-benzothiazol-2-yl) -2,4,6-trimethylbenzamide:
N- (7-amino-1,3-benzothiazol-2-yl) -2,4,6-trimethylbenzamide 0.118 g (0.379 mmol) and propionaldehyde 0.14 mL (1.9 mmol) in dichloroethane 5 mL To the solution was added 1 drop of glacial acetic acid and 0.24 g (1.1 mmol) of sodium triacetoxyhydroborate. The mixture was heated at 50 ° C. for 3 hours and an additional 0.14 mL of propionaldehyde was added. The reaction was heated at 50 ° C. for 18 hours and concentrated under reduced pressure. The crude solid was purified by flash chromatography eluting with a 13% ethyl acetate / hexane mixture to give 0.080 g (53%) of the title compound as a cream powder.
MS Calcd .: 395; Found: 396 (M + H).

Example 11
2- (2,4-Dimethylphenoxy) -N, N-dipropyl-1,3-benzothiazol-7-amine:
2-Bromo-7-nitro-1,3-benzothiazole 7-nitro-1,3-benzothiazol-2-ylamine (1.80 g, 9.22 mmol) in acetic acid (AcOH) (20 ml) suspension in H A 48% hydrobromic acid solution dissolved in 2 O (10 ml) was added under ice cooling. Bromine (0.157 ml) was added dropwise and sodium nitrite (177 mg, 23.9 mmol) dissolved in water (1 ml) was added. The temperature was kept at 0-5 ° C. The mixture was stirred for 2 hours under ice cooling and made alkaline by dropwise addition of 6N aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 1.91 g of the title compound.
1 H-NMR (CDCl 3 ) δ 7.68 (1H, m), 8.33 (1H, m), 8.43 (1H, m). MS Calcd: 257; Found: 258 ( M + H ), 260.

2- (2,4-Dimethylphenoxy) -7-nitro-1,3-benzothiazole 2-bromo-7-nitro-1,3-benzothiazole (200 mg, 0.772 mmol), 2,4-dimethylphenol ( A mixture of 0.093 ml, 0.772 mmol) and potassium carbonate (128 mg, 0.772 mmol) in DMF (10 ml) was stirred at 80 ° C. for 15 hours. The mixture was diluted with water and extracted with ethyl acetate (AcOEt). The extract was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with 10% ethyl acetate in n-hexane solution to give 226 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.26 (3H, s), 2.38 (3H, s), 7.10-7.20 (3H, m), 7.55 (1H, t, J = 8.0 Hz), 8.02 (1H, dd, J = 0.8, 8.0 Hz), 8.24 (1H, dd, J = 0.8, 8.0 Hz).
MS Calcd: 300; Found: 301 (M + H).

2- (2,4-dimethylphenoxy) -1,3-benzothiazol-7-amine 2- (2,4-dimethylphenoxy) -7-nitro-1,3-benzothiazole (220 mg, 0.733 mmol) and A mixture of tin (II) chloride dihydrate (6.94 mg, 3.66 mmol) in DMF (10 ml) was stirred at 80 ° C. for 15 hours and diluted with saturated aqueous sodium hydrogen carbonate solution. This aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with 10% ethyl acetate in n-hexane solution to give 226 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.26 (3H, s), 2.36 (3H, s), 3.70 (2H, s), 6.61 (1H, dd, J = 1.6, 8.0 Hz), 7.08 (1H, d, J = 8.0Hz), 7.11 (1H, m), 7.17 (1H, t, J = 8.0 Hz), 7.22 (1H, d, J = 8.0Hz), 7.24 (1H, d, J = 1.6 Hz).
MS Calcd: 270; Found: 271 (M + H).

2- (2,4-Dimethylphenoxy) -N, N-dipropyl-1,3-benzothiazol-7-amine 2- (2,4-dimethylphenoxy) -1,3-benzothiazol-7-amine (54 mg , 0.200 mmol) in dichloromethane (DCM) (3 ml) was added propionaldehyde (0.058 ml, 0.799 mmol) and then after 30 min sodium triacetoxyhydroborate (169 mg, 0.799 mmol) and acetic acid ( 0.023 ml) was added. The mixture was stirred at room temperature for 15 hours. The reaction was quenched with saturated aqueous sodium bicarbonate. This aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with n-hexane solution containing 2% ethyl acetate to give 57 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.85 (6H, t, J = 7.2 Hz), 1.40-1.55 (4H, m), 2.62 (3H, s), 3.25 (3H, s), 3.08 (4H, t, J = 7.2 Hz), 6.87 (1H, d, J = 8.0 Hz), 7.06 (1H, d, J = 8.0 Hz), 7.10 (1H, s), 7.16 (1H, d, J = 8.0 Hz), 7.27 (1H, t, J = 8.0 Hz), 7.37 (1H, d, J = 8.0 Hz).
MS Calcd: 354; Found: 355 (M + H).

Examples 12-14
Example 12
2-[(2,4-Dimethylphenyl) thio] -N, N-dipropyl-1,3-benzothiazol-7-amine (A)

Example 13
2-[(2,4-Dimethylphenyl) sulfinyl] -N, N-dipropyl-1,3-benzothiazol-7-amine (B)

Example 14
2-[(2,4-Dimethylphenyl) sulfonyl] -N, N-dipropyl-1,3-benzothiazol-7-amine (C)
2-[(2,4-Dimethylphenyl) thio] -N, N-dipropyl-1,3-benzothiazol-7-amine (A)
Compound (A) was prepared in the same manner as Example 11.
1 H-NMR (CDCl 3 ) δ 0.79 (6H, t, J = 7.2 Hz), 1.35-1.50 (4H, m), 2.40 (3H, s), 2.48 (3H, s), 3.05 (4H, t, J = 7.2 Hz), 6.82 (1H, d, J = 8.0 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.29 (1H, t, J = 8.0 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 8.0 Hz).
MS Calcd: 370; Found: 371 (M + 1).

2-[(2,4-Dimethylphenyl) sulfinyl] -N, N-dipropyl-1,3-benzothiazol-7-amine (B)
3-Chloroperbenzoic acid (MCPBA) (20 mg, 0.0810 mmol) was replaced with 2-[(2,4-dimethylphenyl) thio] -N, N-dipropyl-1,3-benzothiazol-7-amine (30 mg, 0.0810 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 hours and diluted with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 16 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.81 (6H, t, J = 7.2 Hz), 1.20-1.30 (2H, m), 1.85-2.00 (2H, m), 2.36 (3H, s), 2.49 (3H, s), 3.40-3.60 (4H, m), 6.98 (1H, d, J = 8.0 Hz), 7.06 (1H, d, J = 8.0 Hz), 7.16 (1H, s), 7.39 (1H, t, J = 8.0 Hz), 7.60 (1H, d, J = 8.0 Hz), 7.79 (1H, d, J = 8.0 Hz).
MS Calcd: 386; Found: 387 (M + H).

2-[(2,4-Dimethylphenyl) sulfonyl] -N, N-dipropyl-1,3-benzothiazol-7-amine (C)
MCPBA (50 mg, 0.202 mmol) was added 2-((2,4-dimethylphenyl) thio) -N, N-dipropyl-1,3-benzothiazol-7-amine (30 mg, 0.081 mmol) in dichloromethane (2 ml). ) Added to the solution. The mixture was stirred at room temperature for 18 hours and diluted with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 6.4 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.83 (6H, t, J = 7.6 Hz), 1.10-1.20 (2H, m), 1.95-2.05 (2H, m), 2.38 (3H, s), 2.70 (3H, s), 3.45-3.70 (4H, m), 7.11 (1H, s), 7.22 (1H, d, J = 8.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 7.58 (1H, t, J = 8.0 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.16 (1H, d, J = 8.0 Hz).
MS Calcd: 402; Found: 403 (M + H).

Example 15
N 2 -mesityl-4-methyl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine
4-Methyl-3-nitro-N, N-dipropylaniline To a solution of 4-methyl-3-nitroaniline (2.00 g, 13.1 mmol) in dichloromethane (100 ml) propionaldehyde (3.79 ml, 52.6 mmol) After 30 minutes, sodium triacetoxyhydroborate (11.1 g, 52.6 mmol) and acetic acid (0.75 ml) were added. The mixture was stirred at room temperature for 15 hours. The reaction was quenched with saturated aqueous sodium bicarbonate. This aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with n-hexane containing 2% ethyl acetate to give 2.50 g of the title compound.
1 H-NMR (CDCl 3 ) δ 0.93 (6H, t, J = 7.6 Hz), 1.50-1.65 (4H, m), 2.44 (3H, s), 3.24 (4H, t, J = 7.6 Hz), 6.74 (1H, dd, J = 2.8, 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 7.18 (1H, d, J = 2.8 Hz).
MS Calcd: 236; Found: 237 (M + H).

4-methyl-N 1 , N 1 -dipropyl-benzene-1,3-diamine 4-methyl-3-nitro-N, N-dipropylaniline (2.49 g, 10.5 mmol) and 10% palladium on carbon (1 0.000 g) acetic acid (50 ml) was catalytically hydrogenated and reduced for 18 hours. The catalyst was removed by celite filtration. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography eluting with n-hexane containing 10% ethyl acetate to give 689 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.85-0.95 (6H, m), 1.45-1.60 (4H, m), 2.07 (3H, s), 3.16 (4H, t, J = 7.6 Hz), 3.50 (2H, m), 6.01 (1H, d, J = 2.8 Hz), 6.07 (1H, dd, J = 28, 8.0 Hz), 6.85 (1H, d, J = 8.0 Hz).
MS Calcd: 206; Found: 207 (M + H).

1- (5-dipropylamino-2-methylphenyl) -3-mesitylthiourea 4-methyl-N 1 , N 1 -dipropyl-benzene-1,3-diamine (200 mg, 0.970 mmol) and 2,4 , 6-Trimethylphenyl isothiocyanate (215 mg, 1.21 mmol) in methanol (2 ml) was refluxed for 18 hours. The solvent was evaporated under reduced pressure. The residue was ground in methanol. The solid was collected by filtration and washed with methanol to give 261 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.92 (6H, t, J = 7.2 Hz), 1.56 (6H, s), 1.50-1.65 (4H, m), 2.22 (3H, s), 2.26, 2.27 (3H, s), 2.30-2.40 (4H, m), 6.57, 6.60 (1H, s), 6.80-6.90 (2H, m), 7.15, 7.26 (1H, s), 7.52 (1H, s).
MS Calcd: 383; Found: 384 (M + H).

N 2 -mesityl-4-methyl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine 1- (5-dipropylamino-2-methylphenyl) -3-mesitylthiourea ( A solution of bromine (0.015 ml, 0.287 mmol) in carbon tetrachloride (5 ml) was added dropwise to a mixture of 100 mg, 0.261 mmol) in carbon tetrachloride (10 ml) over 30 minutes. The mixture was refluxed for 18 hours and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under reduced pressure. The residue was purified by chromatography eluting with n-hexane containing 10% ethyl acetate to give 39 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.76-0.82 (6H, m), 1.25-1.45 (4H, m), 1.58 (3H, s), 2.29 (3H, s), 2.30 (3H, s), 2.52 ( 3H, s), 2.90-2.99 (4H, m), 6.71 (1H, d, J = 8.0 Hz), 6.95 (1H, m), 6.98 (2H, s), 7.04 (1H, d, J = 8.0 Hz) ).
MS Calcd: 381; Found: 382 (M + H).

Example 16
N 2- (2,4-dimethylphenyl) -4-methyl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine
The compound of Example 16 was prepared in the same manner as Example 15.
MS Calcd: 367; Found: 368 (M + H).

Examples 17 and 18

Example 17
N 2 -mesityl-6-methyl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine, and Example 18
4-ethoxy -N 2 - mesityl-6-methyl -N 7, N 7 - dipropyl-1,3-benzothiazole-2,7-diamine
4-isothiocyanate-1-methyl-2-nitrobenzene To a mixture of 4-methyl-3-nitroaniline (1.00 g, 6.57 mmol) and triethylamine (2.75 ml, 19.7 mmol) in THF (150 ml ) was added thiophosgene. (0.55 ml) was added dropwise at 0 ° C. After the addition, the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1.04 g of the title compound.
1 H-NMR (CDCl 3 ) δ 2.60 (3H, s), 7.30-7.40 (2H, m), 7.83 (1H, m).

3-mesityl-1- (4-methyl-3-nitrophenyl) thiourea 4-isothiocyanate-1-methyl-2-nitrobenzene (500 mg, 2.58 mmol) and 2,4,6-trimethylaniline (0.329 ml, 2.34 mmol) of methanol (10 ml) was refluxed for 4 hours. The solvent was distilled off under reduced pressure. The residue was triturated in ether. The produced solid was collected by filtration to obtain 550 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.31 (6H, s), 2.33 (3H, s), 2.58 (3H, s), 7.05 (1H, s), 7.30 (1H, d, J = 8.0 Hz), 7.52 (1H, s), 7.79 (1H, d, J = 8.0 Hz), 7.93 (1H, s).
MS Calcd: 329; Found: 330 (M + H).

N-mesityl-6-methyl-7-nitro-1,3-benzothiazol-2-amine 3-mesityl-1- (4-methyl-3-nitrophenyl) thiourea (500 mg, 1.52 mmol) and carbon tetrachloride To a mixture of (25 ml), a solution of bromine (0.097 ml, 1.90 mmol) in carbon tetrachloride (10 ml) was added dropwise over 1 hour. The mixture was refluxed for 18 hours and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under reduced pressure. The residue was triturated in ether. The resulting solid was collected by filtration to give 225 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.30 (6H, s), 2.35 (3H, s), 2.75 (3H, s), 7.01 (2H, s), 7.17 (1H, bs), 7.28 (1H, d, J = 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz).
MS Calcd: 327; Found: 328 (M + H).

N 2 - mesityl-6-methyl -N 7, N 7 - dipropyl-1,3-benzothiazole-2,7-diamine (A) and 4-ethoxy N 2 - mesityl-6-methyl -N 7, N 7 -Dipropyl-1,3-benzothiazole-2,7-diamine (B)
Tin (II) chloride dihydrate (608 mg, 3.21 mmol) was added to an ethanol solution of N-mesityl-6-methyl-7-nitro-1,3-benzothiazol-2-amine (210 mg, 0.641 mmol). Added. The mixture was refluxed for 15 hours. The solvent was distilled off under reduced pressure. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was diluted with a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 ml). To this solution was added propionaldehyde (0.087 ml, 1.21 mmol) and 30 minutes later sodium triacetoxyhydroborate (257 mg, 1.21 mmol) and acetic acid (0.035 ml) were added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with n-hexane solution containing 10% ethyl acetate to obtain 7.1 mg of compound (A) and 11.9 mg of compound (B).
Compound (A):
1 H-NMR (CDCl 3 ) δ 0.75-0.85 (6H, m), 1.25-1.40 (4H, m), 2.31 (6H, s), 2.33 (3H, s), 2.34 (3H, s), 2.90 ( 4H, t, J = 7.6 Hz), 6.99 (2H, s), 7.06 (1H, d, J = 8.0 Hz), 7.15 (1H, d, J = 8.0 Hz), 7.50 (1H, m).
MS Calcd: 381; Found: 382 (M + H).
Compound (B):
1 H-NMR (CDCl 3 ) δ 0.75-0.85 (6H, m), 1.25-1.35 (4H, m), 1.53 (3H, t, J = 7.2 Hz), 2.29 (6H, s), 2.33 (6H, s), 2.84 (4H, t, J = 7.6 Hz), 4.18 (2H, q, J = 7.2 Hz), 6.60 (1H, s), 6.75 (1H, m), 6.98 (2H, s).
MS Calcd: 425; Found: 426 (M + H).

Example 19
N 2 -mesityl-5-methyl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine
Methyl 2-mesitylamino-7-nitro-1,3-benzothiazole-5-carboxylate (A) and methyl 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylate (B)
To a mixture of methyl 3-[[((mesitylamino) carbonothionyl] amino] -5-nitrobenzoate (1.65 g, 4.42 mmol) in carbon tetrachloride (50 ml) prepared in the same manner as in Example 14, bromine ( A solution of carbon tetrachloride (20 ml) in 0.283 ml (1.25 mmol) was added dropwise over 1 hour. The mixture was refluxed for 18 hours and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and then concentrated under reduced pressure. The residue was purified by chromatography eluting with an n-hexane solution containing 20% ethyl acetate to obtain 707 mg of compound (A) and 450 mg of compound (B).
Compound (A):
1 H-NMR (CDCl 3 ) δ 2.30 (6H, s), 2.36 (3H, s), 3.99 (3H, s), 7.04 (2H, s), 8.41 (1H, d, J = 1.6 Hz), 8.70 (1H, d, J = 1.6 Hz).
MS Calcd: 371; Found: 372 (M + H).
Compound (B):
1 H-NMR (CDCl 3 ) δ 2.29 (6H, s), 2.35 (3H, s), 3.98 (3H, s), 7.01 (2H, s), 8.46 (1H, d, J = 2.2 Hz), 8.62 (1H, d, J = 2.2 Hz).
MS Calcd: 371; Found: 372 (M + H).

(2 Meshichiruamino-7-nitro-1,3-benzothiazol-5-yl) methanol
Methyl 2-mesitylamino-7-nitro-1,3-benzothiazole-5-carboxylate (350 mg, 0.942 mmol) in diethyl ether (6 ml) in 2.0 M lithium borohydride in tetrahydrofuran (THF) (1. 41 ml, 2.82 mmol) solution was added. The mixture was stirred at room temperature for 15 hours. The reaction was quenched with saturated NH 4 Cl solution. The aqueous layer was extracted with ethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with 20% ethyl acetate in n-hexane solution to give 189 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.28 (6H, s), 2.38 (3H, s), 4.94 (2H, s), 7.06 (2H, s), 8.25-8.35 (3H, m).
MS Calcd: 343; Found: 344 (M + H).

5-chloromethyl--N- mesityl-7-nitro-1,3-benzothiazol-2-Amin
Thionyl chloride (0.191 ml, 2.62 mmol) was added to a chloroform solution of (2-mesitylamino-7-nitro-1,3-benzothiazol-5-yl) methanol (180 mg, 0.524 mmol). The mixture was stirred at room temperature for 18 hours and at 60 ° C. for 24 hours. The mixture was poured into water and neutralized with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with 20% ethyl acetate in n-hexane solution to give 122 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.29 (6H, s), 2.36 (3H, s), 4.67 (2H, s), 7.03 (2H, s), 7.80 (1H, d, J = 1.6 Hz), 8.08 (1H, d, J = 1.6 Hz).
MS Calcd: 361; Found: 362 (M + H), 364.

5-methyl -N- mesityl-7-nitro-1,3-benzothiazol-2-Amin
To a solution of 5-chloromethyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (120 mg, 0.332 mmol) in dimethyl sulfoxide (DMSO) (2 ml), sodium borohydride (25 mg,. 663 mmol) was added. The mixture was stirred at room temperature for 3 hours, diluted with water and neutralized with 1N HCl solution. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography eluting with n-hexane solution containing 2% ethyl acetate to give 45 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 2.28 (6H, s), 2.37 (3H, s), 2.60 (3H, s), 7.05 (2H, s), 8.01 (1H, s), 8.16 (1H, s) , 8.28 (1H, s).
MS Calcd: 327; Found: 328 (M + H).

N 2 - mesityl-5-methyl-1,3-benzothiazole-2,7-diamines
5-Methyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (45 mg, 0.137 mmol) and tin (II) chloride dihydrate (124 mg, 0.550 mmol) in DMF (2 ml) ) The mixture was heated at 80 ° C. for 1 hour. The mixture was poured into ice and 1N NaOH solution was added to make the pH slightly alkaline (pH 7-8). The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with 20% ethyl acetate in n-hexane solution to give 10 mg of the title compound.
MS Calcd: 297; Found: 298 (M + H).

N 2 - mesityl-5-methyl -N 7, N 7 - dipropyl-1,3-benzothiazole-2,7-diamines
To a solution of N 2 -mesityl-5-methyl-1,3-benzothiazole-2,7-diamine (10 mg, 0.0336) in dichloromethane (1 ml) was added propionaldehyde (0.012 ml, 0.168 mmol), After 30 minutes, sodium triacetoxyhydroborate (29 mg, 0.135 mmol) and acetic acid (0.0039 ml) were added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was pulverized in n-hexane. The resulting solid was collected by filtration to give 6.8 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.80-1.00 (6H, m), 1.35-1.45 (4H, m), 2.29 (6H, s), 2.33 (3H, s), 2.37 (3H, s), 2.95- 3.05 (4H, m), 6.55 (1H, s), 6.98 (2H, s), 7.02 (1H, s).
MS Calcd: 381; Found: 382 (M + H).

Example 2 0
2- (Mesitylamino) -5-nitro-N, N-dipropyl-1,3-benzothiazole-7-carboxamide
2-Mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylic acid
1N NaOH solution in a mixture of methyl 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylate (230 mg, 0.619 mmol) (prepared in Example 19), methanol (5 ml) and THF (5 ml) (2.48 ml, 2.48 mmol) was added. The mixture was stirred at 50 ° C. for 3 hours. The solvent was removed in vacuo and the aqueous residue was neutralized with 1N HCl solution. The produced precipitate was collected by filtration and dried under reduced pressure to obtain 177 mg of the title compound.
1 H-NMR (DMSO-d 6 ) δ 2.15 (6H, s), 2.26 (3H, s), 7.01 (2H, s), 8.31 (2H, m), 10.00 (1H, m).

To a solution of 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylic acid (90 mg, 0.252 mmol) in DMF (2 ml) was added diethyl cyanophosphate (0.042 ml, 0.277 mmol), dipropylamine ( 0.039 ml, 0.277 mmol) and triethylamine (0.74 ml, 0.277 mmol) were added. The mixture was stirred at room temperature for 18 hours and diluted with water. The aqueous solution was extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with 20% ethyl acetate in n-hexane solution to give 70 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.85-1.00 (6H, m), 1.60-1.65 (4H, m), 2.27 (6H, s), 2.33 (3H, s), 3.36 (4H, m), 6.99 ( 2H, s), 7.12 (1H, m), 7.96 (1H, d, J = 1.6 Hz), 8.35 (1H, d, J = 1.6 Hz).
MS Calcd: 440; Found: 441 (M + H).

Example 21
5-amino-2- (Meshichiruamino) -N, N-dipropyl-1,3-benzothiazol-7 Karubokishiami de
A mixture of 2- (mesitylamino) -5-nitro-N, N-dipropyl-1,3-benzothiazole-7-carboxamide (61 mg, 0.139 mmol) and 10% palladium on carbon (30 mg) in ethanol (10 ml) was added. Hydrogenated for 4 hours. The catalyst was removed by celite filtration. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography eluting with 20% ethyl acetate in n-hexane solution to give 40 mg of the title compound.
1 H-NMR (CDCl 3 ) δ 0.80-0.90 (6H, m), 1.59 (4H, m), 2.26 (6H, s), 2.31 (3H, s), 3.30 (4H, m), 3.71 (2H, m), 6.45 (1H, d, J = 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 6.95 (2H, s).
MS Calcd: 410; Found: 411 (M + H).

Example 22
5- (acetylamino) -2- (mesitylamino) -N, N-dipropyl-1,3-benzothiazole-7-carboxamide (A) and Example 23
5- (acetylamino) -2- [acetyl (mesityl) amino] -N, N-dipropyl-1,3-benzothiazole-7-carboxamide (B)
Acetyl chloride (0.0029 ml, 0.0402 mmol) was added to 5-amino-2- (mesitylamino) -N, N-dipropyl-1,3-benzothiazole-7-carboxamide (15 mg, 0.0365 mmol) and triethylamine (0. 0056 ml, 0.0402 mmol) in THF (1 ml). The mixture was stirred at room temperature for 3 hours and diluted with water. The aqueous solution was extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography eluting with an n-hexane solution containing 20% ethyl acetate to obtain 5.8 mg of compound (A) and 5.1 mg of compound (B) .
Compound (A) :
1 H-NMR (CDCl 3 ) δ 0.80-0.95 (6H, m), 1.50-1.80 (4H, m), 2.19 (3H, s), 2.25 (6H, s), 2.30 (3H, s), 3.34 ( 4H, m), 6.93 (2H, s), 7.51 (2H, s), 7.70 (1H, m).
MS Calcd: 452; Found: 453 (M + H).
Compound (B) :
1 H-NMR (CDCl 3 ) δ 0.70-1.10 (6H.m), 1.50-1.80 (4H, m), 2.05 (3H, s), 2.07 (6H, s), 2.11 (3H, s), 2.38 ( 3H, s), 3.20-3.55 (4H, m), 7.04 (2H, s), 7.80 (1H, s), 7.97 (1H, s).
MS Calcd: 494; Found: 495 (M + H).

Example 24
7-((dipropylamino) methyl) -N-mesityl-1,3-benzothiazol-2-amine:
3- (tert-Butyldimethylsilyloxymethyl) aniline:
To a solution of 1.00 g (8.1 mmol) of 3-hydroxymethylaniline in 25 mL of DMF, 0.61 g (8.9 mmol) of imidazole and 1.35 g (8.9 mmol) of tert-butyldimethylsilyl chloride were added. The reaction was stirred at room temperature for 18 hours and poured into 12 volumes of water. The product was extracted with ether, the organic layers were combined, washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated to give a golden oil. This oil was purified by flash chromatography eluting with a 20% ethyl acetate / hexane mixture to give 1.2 g (62%) of the title compound as a colorless oil.
1 H NMR (CDCl 3 ) δ 0.00 (s, 6H), 0.84 (s, 9H), 4.48 (s, 2H), 4.93 (s, 2H), 6.36 (d, J = 7.6 Hz, 2H), 6.45 ( s, 1H), 6.89 (t, J = 7.6 Hz, 1H).

1- [3- (tert-butyldimethylsilyloxymethyl) phenyl] -3-mesitylthiourea:
To a solution of 0.45 g (1.9 mmol) of 3- (tert-butyldimethylsilyloxymethyl) aniline in 3 mL of methanol was added 0.67 g (3.8 mmol) of mesityl isothiocyanate. The mixture was heated to reflux for 18 hours. The mixture was concentrated and purified by flash chromatography eluting with a 16% ethyl acetate / hexane mixture to give the title compound 0.56 (71%) as a sticky white solid.
MS Calcd .: 414; Found: 415 (M + H).

1- (3-Hydroxymethylphenyl) -3-mesitylthiourea:
10 drops of concentrated hydrochloric acid were added to a solution of 0.56 g (0.1.4 mmol) of 1- [3- (tert-butyldimethylsilyloxymethyl) phenyl] -3-mesitylthiourea in 10 mL of ethanol. After 30 minutes, the reaction mixture was diluted with water and the produced precipitate was collected to give 0.35 g (86%) of the title compound as a white powder.
MS Calcd .: 300; Found: 301 (M + H).

7- (Hydroxymethyl) -N-mesityl-1,3-benzothiazol-2-amine:
To a solution of 0.25 g (0.83 mmol) of 1- (3-hydroxymethylphenyl) -3-mesitylthiourea in 5 mL of glacial acetic acid was added 47 μL (0.91 mmol) of bromine. The reaction was stirred for 5 minutes and concentrated in vacuo to give the title compound and its regioisomeric O-acetate. The mixture was stirred for 1 hour over potassium carbonate in methanol. The mixture was concentrated under reduced pressure, suspended in dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 33-66% ethyl acetate / hexanes gradient mixture to give 0.070 g (28%) of the title compound as a white solid.
MS Calcd .: 298; Found: 299 (M + H).

7- (Bromomethyl) -N-mesityl-1,3-benzothiazol-2-amine:
To a solution of 7- (hydroxymethyl) -N-mesityl-1,3-benzothiazol-2-amine 0.065 g (0.22 mmol) in 2 mL of dichloromethane was added 58 μL (0.72 mmol) of pyridine and 0.24 mL of phosphorus tribromide ( 0.24 mmol) (1M dichloromethane solution) was added. The reaction solution was stirred at room temperature for 8 hours, and a saturated aqueous sodium carbonate solution was added to stop the reaction. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.045 g (57%) of the title compound. This was for the Ku used such that the further purification.
MS Calcd .: 313; Found: 314 (M + H).

7-((dipropylamino) methyl) -N-mesityl-1,3-benzothiazol-2-amine:
To a solution of 0.045 g (0.12 mmol) of 7- (bromomethyl) -N-mesityl-1,3-benzothiazol-2-amine in 0.5 mL of acetonitrile and 2 mL of dichloromethane was added 0.086 g (0.62 mmol) of potassium carbonate and di 85 μL (0.62 mmol) of propylamine was added. The reaction was stirred for 40 minutes, diluted with dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 25% ethyl acetate / hexane mixture to give 0.027 g (57%) of the title compound as a pale yellow powder.
1 H NMR (CDCl 3 ) δ 0.76 (t, J = 7.4 Hz, 6H), 1.40 (q, J = 7.4 Hz, 4H), 2.30-2.34 (m, 13H), 3.58 (s, 2H), 6.95- 7.01 (m, 3H), 7.18 (t, J = 7.8 Hz, 1H), 7.23-7.33 (m, 1H), 8.12 (br s, 1H).
MS Calcd .: 381; Found: 382 (M + H).

Example 25
N 2 -mesityl-N 7 , N 7 -dipropyl-1,3-benzothiazole-2,7-diamine
2-Amino-6-nitrophenol:
A suspension of 5.0 g (27 mmol) of 2,6-dinitrophenol, ammonium hydroxide (3 ml) and 14.3 g (270 mmol) of ammonium chloride in 30 ml of water was heated at 70 ° C. An aqueous solution of sodium sulfite 9 hydrate (24.19 g, 100 mmol) was added and the resulting mixture was stirred at 70 ° C. for 2 hours. The reaction was cooled to room temperature, acidified with 2N HCl (pH 3.2), and the brown precipitate was filtered off. The filtrate was extracted with chloroform (6 × 75 ml), the organic layer and the precipitate were combined and dried under reduced pressure to give 2.5 g (60%) of product as a dark brown solid.
1 H NMR (CDCl 3 ) δ 4.09 (s, 2H), 6.78 (t, 1H, J = 8.2 Hz), 6.95 (d, 1H, J = 7.8 Hz), 7.47 (d, 1H, J = 8.6 Hz) , 10.73 (s, 3H).

1- (2-hydroxy-3-nitrophenyl) -3-mesitylthiourea:
To an ethanol mixture containing 0.10 g (0.65 mmol) of 2-amino-6-nitrophenol and 0.14 g (1.3 mmol) of sodium carbonate, 0.14 g of 2-isothiocyanate-1,3,5-trimethylbenzene ( 0.78 mmol) was added. The reaction was heated to reflux for one day. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by Biotage chromatography eluting with 20% ethyl acetate / dichloromethane to give 0.17 g (80%) of product.
MS Calcd .: 331; Found: 332 (M + H).

N-mesityl-7-nitro-1,3-benzoxazol-2-amine:
0.10 g (0.36 mmol) of mercury (II) chloride was added to an acetonitrile solution containing 0.06 g (0.18 mmol) of 1- (2-hydroxy-3-nitrophenyl) -3-mesitylthiourea, and a mixed solution Was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a celite packed column. The filtrate was concentrated under reduced pressure and the residue was purified by Biotage chromatography eluting with 20% ethyl acetate / dichloromethane to give 0.047 g (90%) of product.
1 H NMR (CDCl 3 ) δ 2.29 (s, 6H), 2.32 (s, 3H), 6.99 (s, 2H), 7.30 (t, 1H, J = 8.2 Hz), 7.77 (d, 1H, J = 8.1 Hz), 7.78 (d, 1H, J = 8.6 Hz).
MS Calcd .: 297; Found: 298 (M + H).

N 2 -mesityl-N 7 , N 7 -dipropyl-1,3-benzoxazole-2,7-diamine:
To the flask was added 0.10 g (0.34 mmol) of N-mesityl-7-nitro-1,3-benzoxazol-2-amine and 40 ml of methanol. The flask was purged with nitrogen gas and 0.01 g of 10% palladium on carbon was added. The flask was evacuated and pressurized with hydrogen to 2-3 psig and stirred for 1 hour. After confirming the completion of the reaction by HPLC, the reaction solution was filtered with GF / F filter paper. The filtrate was transferred to a round bottom flask and 0.1 ml (1.7 mmol) propionaldehyde, 0.1 g (1.7 mmol) NaBH 3 CN and 1 ml acetic acid were added. The mixture was stirred overnight and diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate. Filtration, removal of the solvent and purification of the residue by chromatography by Biotage eluting with 5% methanol / dichloromethane gave 0.11 g of product (90% over 2 steps).
1 H NMR (CDCl 3 ) δ 0.74 (t, 6H, J = 7.2 Hz), 1.47 1.53 (m, 4H), 2.27 (s, 6H), 2.29 (s, 3H), 3.18 (t, 4H, J = 7.8 Hz), 6.34 (d, 1H, J = 8.1 Hz), 6.70 (d, 1H, J = 7.0 Hz), 6.93 (s, 2H), 6.98 (t, 1H, J = 8.1 Hz).
MS Calcd .: 351; Found: 352 (M + H).

Example 26
N 2 -mesityl-1-methyl-N 7 , N 7 -dipropyl-1H-benzimidazole-2,7-diamine:
2,6-dinitro-N-methylaniline:
Methylamine (4.5 ml of a 2.0 M THF solution) was added to a 40 ml THF solution of 2-chloro-1,3-dinitrobenzene (0.90 g, 4.4 mmol) and stirred for 30 minutes. The reaction was stopped by adding water and ether. The aqueous layer was separated and extracted twice with ether. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was removed by filtration, and the residue was purified by chromatography by Biotage, eluting with 20% ethyl acetate / dichloromethane to give 0.80 g (91%) of product.
1 H NMR (CDCl 3 ) δ 2.89 (d, 3H, J = 5.6 Hz), 6.75 (t, 1H, J = 8.1 Hz), 8.18 (d, 2H, J = 8.3 Hz).

N 2 -methylbenzene-1,2,3-triamine:
To the flask, 0.30 g (1.5 mmol) of 2,6-dinitro-N-methylaniline and 40 ml of methanol were added. The flask was purged with nitrogen gas and 0.03 g of 10% palladium carbon was added. The flask was evacuated and pressurized with 2-3 psig hydrogen and stirred for 1 hour. After confirming completion of the reaction by HPLC, the reaction solution was filtered with GF / F filter paper. The filtrate was evaporated to dryness to give 0.2 g (95%) of product.
MS Calcd .: 137; Found: 138 (M + H).

1- (3-amino-2-methylaminophenyl) -3-mesitylthiourea:
2 -isothiocyanate-1,3,5-trimethylbenzene was added to an ethanol mixture of 0.25 g (1.82 mmol) of N 2 -methylbenzene-1,2,3-triamine and 0.40 g (3.7 mmol) of sodium carbonate. 0.32 g (1.86 mmol) was added. The reaction was heated to reflux and the solvent was removed under reduced pressure. The residue was purified by Biotage chromatography eluting with 20% ethyl acetate / dichloromethane to give 0.34 g (60%) of product.
1 H NMR (CDCl 3 ) δ 2.19 (s, 6H), 2.26 (s, 3H), 3.68 (s, 3H), 3.85 (s, 4H), 6.20 (d, 2H, J = 8.1 Hz), 6.87 ( s, 2H), 6.95 (t, 1H, J = 8.1 Hz), 7.07 (s, 1H).
MS Calcd .: 314; Found: 315 (M + H).

N 2 -mesityl-1-methyl-1H-benzimidazole-2,7-diamine:
To an acetonitrile solution containing 0.25 g (0.79 mmol) of 1- (3-amino-2-methylaminophenyl) -3-mesitylthiourea was added 0.52 g (1.6 mmol) of mercury (II) chloride, and the mixture Was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a celite packed column. The filtrate was concentrated under reduced pressure, and the residue was purified by Biotage chromatography eluting with 20% ethyl acetate / dichloromethane to give 0.12 g (55%) of product.
1 H NMR (CD 3 OD) δ 2.27 (s, 6H), 2.36 (s, 3H), 4.13 (s, 3H), 7.13 (s, 2H), 7.24 7.26 (m, 2H), 7.33 (t, 1H , J = 8.1 Hz).
MS Calcd .: 280; Found: 281 (M + H).

N 2 -mesityl-1-methyl-N 7 , N 7 -dipropyl-1H-benzimidazole-2,7-diamine:
To a methanol (5 ml) solution containing 0.05 g (0.18 mmol) of N 2 -mesityl-1-methyl-1H-benzimidazole-2,7-diamine, 0.03 ml (0.54 mmol) of propionaldehyde, cyanotrihydro 0.03 g (0.54 mmol) sodium borate and 0.1 ml acetic acid were added. The mixture was stirred overnight, diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate. Filtration was performed, the solvent was distilled off, and the residue was purified by Biotage chromatography eluting with 5% methanol / dichloromethane to obtain 0.04 g (70%) of the product.
1 H NMR (CDCl 3 ) δ 0.85 (t, 6H, J = 7.3 Hz), 1.46 1.53 (m, 4H), 2.22 (s, 6H), 2.28 (s, 3H), 2.98 (s, 4H), 3.94 (s, 3H), 6.86 (d, 1H, J = 7.8 Hz), 6.92 (s, 2H), 6.99 (t, 1H, J = 8.1 Hz), 7.20 (s, 1H).
MS Calcd .: 364; Found: 365 (M + H).

The compounds of Examples 27-30 shown in Table 2 were prepared in the same manner as described in Example 26.
Table 2

Example 31
N 7 -cyclopropylmethyl-N 2 -mesityl-1-methyl-N 7 -propyl-1H-benzimidazole-2,7-diamine:
7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one:
N 2 dissolved in THF350mL - N, N'- carbonyl Le diimidazole 11.3g of (70 mmol) was added to methyl benzene-1,2,3-triamine 9.6 g (70 mmol). The reaction mixture was stirred for 18 hours and concentrated in vacuo. The crude solid was triturated in dichloromethane and collected by filtration to give 6.94 g (61%) of the title compound as a brown powder.
1 H NMR (DMSO-d 6 ) δ 3.51 (s, 3H), 4.85 (s, 2H), 6.30 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 6.68 ( t, J = 8.0, 1H), 10.55 (s, 1H).

1-methyl-7- (propylamino) -1,3-dihydro-2H-benzimidazol 2-one:
To a solution of 7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 0.87 g (5.3 mmol) in methanol 50 mL, propionaldehyde 1.94 mL (26.7 mmol) and cyanotrihydroboric acid Sodium 1.0 g (16 mmol) was added. The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. The crude solid was partitioned between water and ethyl acetate, the bilayer mixture was filtered to remove the powder and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with a 50% ethyl acetate / hexane mixture to give 0.69 g (63% ) As a cream powder.
MS Calcd .: 205; Found: 206 (M + H).

7-Benzyl (propyl) amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one:
1-Methyl-7- (propylamino) -1,3-dihydro-2H-benzimidazol-2-one 0.69 g (3.4 mmol) in methanol 20 mL solution, benzaldehyde 0.68 mL (6.7 mmol), glacial acetic acid 10 Drops and 0.63 g (10 mmol) of sodium cyanotrihydroborate were added. The mixture was stirred at 50 ° C. for 18 hours, and 0.68 mL of benzaldehyde, 10 drops of glacial acetic acid and 0.63 g of sodium cyanotrihydroborate were added. The mixture was heated for an additional 24 hours and 0.68 mL of benzaldehyde, 10 drops of glacial acetic acid and 0.63 g of sodium cyanotrihydroborate were added. The reaction was cooled to room temperature and volatiles were removed under reduced pressure. The crude solid was partitioned between water and ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and then flash chromatographed eluting with 33% ethyl acetate / hexane mixture. To give 0.65 g (65%) of the title compound as a colorless sticky solid.
MS Calcd .: 295; Found: 296 (M + H).

N 7 -benzyl-2-chloro-1-methyl-N 7 -propyl-1H-benzimidazole 7-amine:
A solution of 0.65 g (2.2 mmol) of 7-benzyl (propyl) amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 10 mL of phosphorus oxychloride was heated to 100 ° C. After stirring for 24 hours, the mixture was concentrated under reduced pressure and quenched with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.56 g (81%) of the title compound as a sticky yellow oil. This crude oil was used in the production of E without further purification.
MS Calcd .: 313; Found: 314 (M + H).

N 7 -benzyl-N 2 -mesityl-1-methyl-N 7 -propyl-1H-benzimidazole-2,7-diamine:
A solution of 0.56 g (1.8 mmol) of N 7 -benzyl-2-chloro-1-methyl-N 7 -propyl-1H-benzimidazole 7-amine in 0.75 mL (5.4 mmol) of mesitylamine was heated to 130 ° C. . After stirring for 24 hours, the mixture was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to a tan solid. The resulting solid was purified by flash chromatography eluting with 1.3% methanol / dichloromethane mixture to give 0.59 g (80%) of the title compound as a cream solid.
MS Calcd .: 412; Found: 413 (M + H).

N 2 -mesityl-1-methyl-N 7 -propyl-1H-benzimidazole-2,7-diamine:
N 7 - benzyl -N 2 - mesityl-1-methyl -N 7 - 20% methanol 30mL solution of propyl -1H- benzimidazole-2,7-diamine 0.50 g (1.2 mmol) Pearlman catalyst (50% wet ) 0.43 g (10 mol% Pd) was added. The reaction was kept under a hydrogen atmosphere with a balloon and stirred at room temperature for 48 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography eluting with a 7% methanol / dichloromethane mixture gave 0.23 g (58%) of the title compound as a cream colored solid.
MS Calcd .: 322; Found: 323 (M + H).

N 7 -cyclopropylmethyl-N 2 -mesityl-1-methyl-N 7 -propyl-1H-benzimidazole-2,7-diamine:
N 2 - mesityl-1-methyl -N 7 - propyl -1H- benzimidazole-2,7-diamine 0.041 g (0.13 mmol) of methanol 2mL solution cyclopropane carboxaldehyde 95 [mu] L (1.3 mmol), glacial acetic acid 200 μL and 0.032 g (0.51 mmol) of sodium cyanotrihydroborate were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. The crude solid was partitioned between saturated sodium bicarbonate and dichloromethane, the organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC to afford 0.026 g (42%) of the title compound. Was obtained as a sticky colorless solid.
MS Calcd .: 376; Found: 377 (M + H).

The compounds of Examples 32-60 shown in Table 3 were prepared in the same manner as described in Example 31. Compounds 32-53 were purified by reverse phase HPLC (CH 3 CN containing 0.1% TFA / water containing 0.1% TFA) to obtain a TFA salt.
Table 3






Example 61
N 2 - (2,4-dimethylphenyl) -N 5, N 5 - dipropyl imidazo [1,2-a] pyridine-2,5-diamine:
Imidazo [1,2-a] pyridin-5-amine:
2,6-diaminopyridine (5.0 g, 46 mmol) and chloroacetaldehyde (50 wt% aqueous solution, 6.4 mL, 50 mmol) were dissolved in absolute ethanol (120 mL). The solution was heated at 75 ° C. for 1 hour. The mixture was cooled and concentrated on a rotary evaporator. The residue was treated with saturated sodium bicarbonate solution and ethyl acetate. The solution was extracted with ethyl acetate (3 times), dried over magnesium sulfate and concentrated to give a brown solid. 4.85 g was isolated (yield 80%).
1 H NMR (CDCl 3 ) δ 4.48 (s, 2H), 6.10 (dd, J = 7.2, 1.2 Hz, 1H), 7.10 7.20 (m, 2H), 7.42 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H).
MS Calcd .: 133; Found: 134 (M + H).

N, N-dipropylimidazo [1,2-a] pyridin-5-amine:
Imidazo [1,2-a] pyridin-5-amine (4.85 g, 36 mmol) was dissolved in DMF (72 mL). Sodium hydride (60% mineral oil, 5.8 g, 146 mmol) was carefully added. The mixture was stirred for 0.5 h at room temperature. 1-Bromopropane (13.2 mL, 145 mmol) was added. After 1 hour, the reaction solution was quenched with water and extracted with ether (4 times). The organic layers were combined, dried over magnesium sulfate and concentrated. Flash chromatography (80-100% ethyl acetate / hexane) gave 7.92 g of the title compound as a brown oil (yield 83%).
1 H NMR (CDCl 3 ) δ 0.88 (t, J = 8.4 Hz, 6H), 1.51 1.57 (m, 4H), 3.06 3.10 (m, 4H), 6.34 (d, J = 6.8 Hz, 1H), 7.14 7.18 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 5.6 Hz, 2H).
MS Calcd .: 217; Found 218 (M + H).

2-Bromo-N, N-dipropylimidazo [1,2-a] pyridin-5-amine:
N, N-dipropylimidazo [1,2-a] pyridin-5-amine (1.0 g, 4.6 mmol) was diluted in DMF (25 mL). The solution was cooled to 0 ° C. N-bromosuccinamide (0.83 g, 4.7 mmol) was added. After 5 minutes, the reaction was quenched with water. The solution was extracted with ether, dried and concentrated. Flash chromatography (40% ethyl acetate / hexane) gave the title compound as a yellow oil. This solidified upon cooling at −20 ° C. overnight. Yield 0.67 g (49% yield).
1 H NMR (CDCl 3 ) δ 0.86 (t, J = 7.6 Hz, 6H), 1.43 1.64 (m, 4H), 2.98 3.13 (m, 4H), 6.40 (d, J = 8.0 Hz, 1H), 7.10 7.14 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H).
MS Calcd .: 296; Found: 296 (M) 298 (M + 2H).

N 2 - (2,4-dimethylphenyl) -N 5, N 5 - dipropyl imidazo [1,2-a] pyridine-2,5-diamine:
2-Bromo-N, N-dipropylimidazo [1,2-a] pyridin-5-amine (C) (0.127 g, 0.43 mmol) was diluted in 2,4-dimethylaniline (2 mL). The solution was heated to 75 ° C. in a sealed tube for 2 hours. The solution was flash chromatographed with basic alumina (20% ethyl acetate / hexane) to give 0.029 g of the title compound as a brown residue (yield 20%).
1 H NMR (CDCl 3 ) δ 0.88 (t, J = 6.8 Hz, 6H), 1.49 1.56 (m, 4H), 2.28 (s, 3H), 2.29 (s, 3H), 3.04 3.07 (m, 4H), 6.12 (s, 1H), 6.30 6.32 (m, 1H), 7.02 7.04 (m, 2H), 7.10 7.12 (m, 2H), 7.22 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H).
MS Calcd .: 336; Found: 337 (M + H).

The compounds of Examples 62-63 shown in Table 4 were prepared in the same manner as described in Example 61.
Table 4

Example 64
(2,4-Dimethylphenyl) (5- (dipropylamino) imidazo [1,2-a] pyridin-2-yl) methanone:
2-Bromo-N, N-dipropylimidazo [1,2-a] pyridin-5-amine (prepared in Example 61) (0.136 g, 0.46 mmol) was dissolved in THF (1 mL). The solution was cooled to -78 ° C. t-Butyllithium (1.7M, 0.57 mL, 0.96 mmol) was added dropwise and the solution was stirred for 1 hour at -78 ° C. 2,4-Dimethylbenzoyl chloride (0.097 g, 0.57 mmol) diluted with 0.5 mL of THF was added to the reaction solution. After 0.5 hour, the reaction was quenched with water and allowed to warm to room temperature. Extraction with ethyl acetate was performed, and the organic layer was dried over magnesium sulfate and concentrated. Flash chromatography (30-40% ethyl acetate / hexane) gave 0.039 g of the title compound (24% yield).
1 H NMR (CDCl 3 ) δ 0.82 (t, J = 7.6 Hz, 6H), 1.32 1.65 (m, 4H), 2.40 (s, 3H), 2.48 (s, 3H), 3.13 3.19 (m, 4H), 6.55 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H).
MS Calcd .: 349; Found: 350 (M + H).

Example 65
2- (2,4-Dimethylphenyl) -N, N-dipropylimidazo [1,2-a] pyridin-5-amine:
2 - blow mode - N, N-dipropyl-imidazo [1,2-a] pyridin-5-amine (prepared in Example 61) (0.17g, 0.57mmol) and 1,2-dimethoxyethane (DME) (1.5 mL). Pd (PPh 3 ) 4 (0.033 g, 0.028 mmol) was added and the reaction was stirred for 15 minutes at 50 ° C. The reaction solution was cooled and a solution of 2,4-dimethylphenylboric acid (0.103 g, 0.69 mmol) in DME (1 mL) was added to the reaction mixture. A solution of KOtBu (0.128 g, 1.14 mmol) in tBuOH (1 mL) was further added to the reaction solution. The reaction was heated at 100 ° C. for 1 hour. The reaction solution was filtered through filter paper and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile containing 0.1% TFA / water containing 0.1% TFA) to give 3.1 mg of the title compound (yield 2%).
MS Calcd .: 321; Found: 322 (M + H).

Example 66
5-fluoro--N 2 - mesityl-1-methyl -N 7, N 7 - dipropyl -1H- benzimidazole-2,7-diamine
2-Chloro-5-fluoro-1,3-dinitrobenzene To a solution of 0.65 g (2.2 mmol) of 4-fluoro-2,6-dinitrophenol in 30 mL of dimethylformamide was added 1.4 mL (15 mmol) of phosphorus oxychloride. . The mixture was heated at 70 ° C. overnight, then cooled to room temperature and quenched with ice. The mixture was diluted with water and the precipitate was collected to give 1.35 g (82%) of the title compound as a cream solid.
1 H NMR (DMSO-d 6 ) δ8.55 (d, J = 1.5 Hz, 1H), 8.57 (d, J = 1.3 Hz, 1H).

4-Fluoro-N-methyl-2,6-dinitroaniline
To a solution of 1.35 g (6.12 mmol) of 2-chloro-5-fluoro-1,3-dinitrobenzene in THF (20 mL) was added 6.1 mL (12 mmol) of 2N methylamine in THF at 0 ° C. The cooling bath was removed and the reaction was stirred at room temperature for 45 minutes. The reaction was concentrated, diluted with ether and washed with saturated sodium bicarbonate solution. The resulting organic layer was dried over sodium sulfate, filtered and concentrated to give 1.30 g (90%) of the title compound as a bright orange powder.
1 H NMR (DMSO-d 6 ) δ 2.70 (d, J = 5.5 Hz, 3H), 8.20 (br s, 1H) 8.29 (d, J = 8.2 Hz, 2H).

1- [3-Amino-5-fluoro-2- (methylamino) phenyl] -3-mesitylthiourea 1.30 g (6.04 mmol) of 4-fluoro-N-methyl-2,6-dinitroaniline in 75 mL of ethanol ), 3.7 mL (36 mmol) of cyclohexene and 5.1 g (2.4 mmol, 40 mol%) of 10% palladium on carbon (50% water, Degussa type). The mixture was refluxed for 2.5 hours and then filtered into a flask containing 0.77 g (7.3 mmol) sodium carbonate and 2-isothiocyanate-1,3,5-trimethylbenzene. The resulting suspension was refluxed for 4 hours, concentrated and suspended in dichloromethane. The slurry was filtered, concentrated and purified by flash chromatography eluting with a 70% hexane / ethyl acetate mixture to give 0.65 g (32%) of the title compound as an off-white solid.
1 H NMR (DMSO-d 6 ) δ2.09 (s, 6H), 2.20 (s, 3H), 3.45 (s, 3H), 5.00 (br s, 4H), 5.78 (d, J = 11.2 Hz, 2H ), 6.79 (s, 2H), 7.93 (br s, 1H).
MS Calcd .: 332; Found: 299 (M + HH 2 S).

5-fluoro--N 2 - mesityl-1-methyl -N 7, N 7 - dipropyl -1H- benzimidazole-2,7-diamine 1- [3-amino-5-fluoro-2- (methylamino) phenyl] To a solution of 0.29 g (0.87 mmol) of -3-mesitylthiourea in 15 mL of acetonitrile was added 1.09 mL (7.9 mmol) of triethylamine, followed by 0.4 g (1.5 mmol) of mercury chloride. After reacting at room temperature for 2 hours, 0.7 g (2.6 mmol) of mercury chloride was further added. After further reaction for 2 hours, the reaction mixture was diluted with water, and the resulting crude 5-fluoro-N 2 -mesityl-1-methyl-1H-benzimidazole-2,7-diamine was collected as a brown precipitate by filtration. did. The resulting crude product was suspended in 50 mL of methanol and treated with 1.6 mL (22 mmol) of propionaldehyde, 3 mL of glacial acetic acid and 1.1 g (17 mmol) of sodium cyanotrihydroborate. The mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. The crude solid was mixed with water and made basic with saturated potassium carbonate solution. The mixture was partitioned between ethyl acetate and separated. The organic layer is washed with brine, dried over sodium sulfate, filtered, concentrated on silica gel and purified by flash chromatography eluting with a 75% hexane / ethyl acetate mixture to give the title compound containing impurities. Got. This material was suspended in hexane and 0.065 g (20%) of the title compound was collected by filtration as a white solid.
1 H NMR (DMSO-d 6 ) δ0.83 (t, J = 7.2 Hz, 6H), 1.43 (q, J = 7.2 Hz, 4H), 2.11 (s, 6H), 2.26 (s, 3H), 2.94 (m, 4H), 3.92 (s, 3H), 6.60 (t, J = 12.3 Hz, 2H), 6.91 (s, 2H), 8.01 (s, 1H).
19 F NMR (DMSO-d 6 ) δ-117.85 (s, 1F).
MS Calcd .: 382; Found: 383 (M + H).

Other Examples Table 5

Example 69
N 7 - butyl -N 2 - mesityl -N 7 - (4-methoxyphenyl) -1-methyl -1H- benzimidazole-2,7-diamine
7-[(4-Methoxyphenyl) amino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7-Amino-1-methyl-1,3-dihydrobenzimidazol-2-one 0 183 g (1.12 mmol), biphenyl-2-yl-dicyclohexylphosphane 0.037 g (0.11 mmol), sodium tert-butoxide 0.237 g (2.47 mmol) and tris (dibenzylidineacetone) dipalladium A mixture of 041 g (0.045 mmol) in 6 mL of THF was treated with 0.14 mL (1.12 mmol) of 4-bromoanisole and heated at 60 ° C. for 18 hours. The reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and purified by flash chromatography eluting with a 97% dichloromethane / methanol mixture to afford 0.126 g (42%) of the title compound as an off-white tan Obtained as a powder.
1 H NMR (DMSO-d 6 ) δ 3.29 (s, 3H), 3.66 (s, 3H), 6.62 (d, J = 8.8 Hz, 2H), 6.70-6.83 (m, 4H), 6.91 (t, J = 7.8 Hz, 1H), 7.30 (s, 1H), 10.85 (s, 1H).
MS Calcd .: 269; Found: 270 (M + H).

7- [Butyl (4-methoxyphenyl) amino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one
7-[(4-Methoxyphenyl) amino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 0.100 g (0.37 mmol) and butyraldehyde 0.13 mL (1.5 mmol) A 15 mL mixture of dichloroethane was treated with 4 drops of surface acetic acid and 0.31 g (1.5 mmol) of sodium triacetoxyhydroborate. The mixture was heated at 70 ° C. for 5 days. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and brine, and dried over sodium sulfate. The solution was filtered, concentrated in vacuo, and the resulting crude oil was purified by flash chromatography eluting with 97% dichloromethane / methanol mixture to afford 0.70 g (45%) of the title compound as a yellow viscous It was obtained as a semi-solid with, but this compound had for things ku further purification.

N-butyl-2-chloro-N- (methoxyphenyl) -1-methyl-1H-benzimidazol-7-amine
A solution of 0.070 g (0.22 mmol) of 7- [butyl (4-methoxyphenyl) amino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of phosphorus oxychloride is heated to 100 ° C. did. After stirring for 2 hours, the mixture was concentrated under reduced pressure, and the reaction was quenched with saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate, and the extract was washed with brine, dried over sodium sulfate, filtered, concentrated on silica gel, and then flash chromatographed to obtain a 85% hexane / ethyl acetate mixture. The title compound containing impurities was obtained by purification with elution. This material was suspended in hexane to give 0.018 g (36%) of the title compound as a colorless oil.
MS Calcd .: 343; Found: 310 (M + H-Cl).

N 7 - butyl -N 2 - mesityl -N 7 - (4-methoxyphenyl) -1-methyl -1H- benzimidazole-2,7-diamine N- butyl-2-chloro -N- (methoxyphenyl) -1 A solution of 0.018 g (0.05 mmol) of methyl-1H-benzimidazol-7-amine in 0.10 mL (0.73 mmol) of mesitylamine was heated to 130 ° C. After stirring for 18 hours, the reaction mixture was dissolved in dichloromethane, purified on silica gel and purified by flash chromatography eluting with a 96% dichloromethane / methanol mixture to give 0.015 g (65%) of the title compound as reddish. Obtained as a tan solid.
1 H NMR (DMSO-d 6 ) δ 0.90 (t, J = 7.2 Hz, 3H), 1.34 (q, J = 7.4 Hz, 2H), 1.62 (m, 2H), 2.10 (s, 6H), 2.26 ( s, 3H), 3.45-3.55 (m, 2H), 3.52 (s, 3H), 3.65 (s, 3H), 6.48 (d, J = 9.0 Hz, 2H), 6.70 (d, J = 7.4 Hz, 1H ), 6.77 (d, J = 8.2 Hz, 2H), 6.95-7.04 (m, 2H), 7.93 (s, 1H).
MS Calcd .: 442; Found: 443 (M + H).

The following example compounds were prepared according to the method described in Example 26.
Table 6











Example 113
4-Bromo -N 2 - mesityl-1-methyl -N 7, N 7 - dipropyl -1H- benzimidazole-2,7-diamine

4-Bromo-7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazole-2 A mixed solution of -one (200 mg, 0.809 mmol), N-bromosuccinimide (216 mg, 1.21 mmol) and catalytic amount of benzoyl peroxide in carbon tetrachloride (20 ml) was refluxed for 60 hours and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% ethyl acetate / n-hexane to give 73 mg (28%) of the title compound.
1 H-NMR (CDCl 3 ) δ0.84 (6H, t, J = 7.2 Hz), 1.35-1.48 (4H, m), 2.85-2.95 (4H, m), 3.71 (3H, s), 6.81 (1H , d, J = 8.4 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.82 (1H, s).
MS Calcd .: 325; Found: 326 (M + H), 328.

4-Bromo-2-chloro-1-methyl-N, N-dipropyl-1H-benzimidazol-7-amine 4-bromo-7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazole A mixture of 2-one (210 mg, 0.644 mmol) and phosphorus oxychloride (3.0, 32 mol) was refluxed for 18 hours with stirring, and then evaporated to dryness under reduced pressure. The residue was diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 220 mg (99%) of the title compound. The residue was used in the next reaction without further purification.
1 H-NMR (DMSO-d 6 ) δ 0.80 (6H, t, J = 7.2 Hz), 1.35-1.45 (4H, m), 2.97 (4H, m), 4.08 (3H, s), 7.05 (1H, d, J = 8.0 Hz), 7.38 (1H, d, J = 8.0 Hz).
MS Calcd .: 343; Found: 344 (M + H), 346.

4-Bromo -N 2 - mesityl-1-methyl -N 7, N 7 - dipropyl -1H- benzimidazole-2,7-diamines
A mixture of 4-bromo-2-chloro-1-methyl-N, N-dipropyl-1H-benzimidazol-7-amine (220 mg, 0.638 mmol) and mesitylamine (1.79 ml, 12.8 mmol) at 120 ° C. Heated for 60 hours. The reaction mixture was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5% n-hexane / ethyl acetate to give the title compound.
1 H-NMR (CDCl 3 ) δ 0.80 (6H, t, J = 7.2 Hz), 1.42 (4H, q, J = 7.2 Hz), 2.20 (6H, s), 2.30 (3H, s), 2.91 (4H , m), 3.53 (3H, s), 6.05 (1H, s), 6.71 (1H, d, J = 8.4 Hz), 6.91 (2H, s), 7.19 (1H, d, J = 8.4 Hz).
MS Calcd .: 442; Found: 443 (M + H), 445.

The compounds of Examples 114-117 shown in Table 7 were prepared in the same manner as described in Example 1.
Table 7

The compounds of Examples 118-122 shown in Table 8 were prepared in the same manner as described in Example 1.
Table 8

Example 123
N 2 - (4-bromo-2-methoxy-6-methylphenyl) -N 7, N 7 - bis (2-methoxyethyl) -1-methyl -1H- benzimidazole-2,7-diamine
To a 25 mL chloroform solution of 200 mg (1.66 mmol) of 1,1,3-trimethoxypropane was added 5 g (1.66 mmol) of iron (II) chloride (5% by weight) supported on silica, and the suspension was cooled to room temperature. For several hours. The suspension was filtered and concentrated in vacuo to about 5mL, N 2 - (4- bromo-2-methoxy-6-methyl-phenyl) -1-methyl -1H- benzimidazole-2,7-diamine 200 mg (0 .55 mmol), 1 mL of acetic acid and 2.5 g (5.08 mmol) of MP-CNBH 3 in 10 mL of methanol and stirred overnight. The aldehyde synthesis was repeated daily for 7 days and added to the reaction solution. The reaction solution was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography eluting with 40% ethyl acetate / hexane solution containing 2% ammonium hydroxide to give 47 mg (18%) of the title compound.
1 H NMR (CDCl 3 ) δ 2.19 (s, 3H), 3.28 (s, 6H), 3.33 (br s, 4H), 3.41 (br s, 4H), 3.82 (s, 3H), 4.06 (s, 3H ), 5.85 (s, 1H), 6.92-6.97 (m, 2H), 7.02-7.04 (m, 2H), 7.30 (d, J = 7.7 Hz, 1H); MS Calcd .: 476; Found: 477 (M + H).

The following compounds were prepared in the same manner.
Table 9

Example 126
4-[[2-[(4-Bromo-2-methoxy-6-methylphenylamino) -1-methyl-1H-benzimidazol-7-yl] (isopropyl) amino] butanoic acid
100 mg (0.20 mmol) of methyl 4-[[2- (4-bromo-2-methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazol-7-yl] (isopropyl) amino] butanoate To a solution of 5 mL of tetrahydrofuran and 2.5 mL of water, 83 mg (2.0 mmol) of lithium hydroxide monohydrate was added. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was diluted with water, carefully adjusted to pH 7 with 1N aqueous hydrochloric acid solution, and the resulting suspension was filtered. The solid was washed with water and dried under high vacuum to give 95 mg (98%) of the title compound.
MS Calcd .: 488; MS Found: 489 (M + H).

Example 127
4-[[2-[(4-Bromo-2-methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazol-7-yl] (isopropyl) amino] -N-methylbutanamide
4-[[2-[(4-Bromo-2-methoxy-6-methylphenylamino) -1-methyl-1H-benzimidazol-7-yl] (isopropyl) amino] butanoic acid 25 mg (0.050 mmol), Dichloroethylamine 0.044 mL (0.26 mmol) and hexafluorophosphoric acid O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium (HATU) 58 mg To a solution of 15 mmol), 0.128 mL (0.26 mmol) of methylamine (2M tetrahydrofuran solution) was added. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 8% methanol / dichloromethane solution to give 42 mg (82%) of the title compound.
MS Calcd .: 501; MS Found: 502 (M + H).

The following compounds were prepared in the same manner.
Table 10

Example 136
N 7 - (2-aminoethyl) -N 2 - (4- bromo-2-methoxy-6-methylphenyl) -N 7 - isopropyl-1-methyl -1H- benzimidazole-2,7-diamine hydrochloride
N 2 - (4-bromo-2-methoxy-6-methylphenyl) - N 7 - 1 containing 2 drops of acetic acid isopropyl-1-methyl -1H- benzimidazole-2,7-diamine 100 mg (0.25 mmol) , 2-Dichloroethane 2 mL solution was added (2-oxoethyl) carbamic acid tert-butyl ester 79 mg (0.50 mmol) 1,2-dichloroethane 1 mL solution. Then, 158 mg (0.74 mmol) of sodium triacetoxyhydroborate was added to the reaction mixture. After stirring the reaction for several hours, another 2 equivalents of aldehyde was added to the reaction. The reaction solution was stirred at room temperature overnight, and another 2 equivalents of aldehyde was further added to the reaction solution, followed by stirring for several hours. The reaction was then heated at 80 ° C. overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in dichloromethane, and 1 ml (13 mmol) of trifluoroacetic acid was added. The mixture was stirred at room temperature for several hours and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound as the trifluoroacetate salt. The salt was dissolved in methanol and treated with hydrochloric acid (1N diethyl ether solution). The solution was concentrated under reduced pressure to give 20 mg (18%) of the title compound as the hydrochloride salt.
MS Calcd .: 445; MS Found: 446 (M + H).

Example 137
N 2 - (4-bromo-2-methoxy-6-methylphenyl) -N 7 - [2- (dimethylamino) ethyl] -N 7 - isopropyl-1-methyl -1H- benzimidazole-2,7-diamine Hydrochloride
N 7 - (2-aminoethyl) -N 2 - (4- bromo-2-methoxy-6-methylphenyl) -N 7 - isopropyl-1-methyl -1H- benzimidazole-2,7-diamine 10 mg (0 0.02 mL (0.22 mmol) of formaldehyde (37 wt% aqueous solution) and 24 mg (0.11 mmol) of sodium triacetoxyhydroborate were added to a solution of 0.022 mmol). The reaction was stirred at room temperature for 2 hours and diluted with dichloromethane. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound as the trifluoroacetate salt. The salt was dissolved in methanol and treated with hydrochloric acid (1N diethyl ether solution). The solution was concentrated under reduced pressure to give 4 mg (38%) of the title compound as the hydrochloride salt.
MS Calcd .: 473; MS Found: 474 (M + H).

Example 138
N 2 - (4-chloro-2-methoxy-6-methylphenyl) -N 7 - (4- chlorophenyl) -N 7 - isopropyl-1-methyl -1H- benzimidazole-2,7-diamine hydrochloride

7-[(4-Chlorophenyl) amino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7-Amino-1-methyl-1,3-dihydrobenzimidazol-2-one (5 0.0 g, 30.6 mmol), biphenyl-2-yl-dicyclohexylphosphine (0.537 g, 1.53 mmol), sodium tert-butoxide (7.4 g, 2.5 mmol), tris (dibenzylidineacetone) dipalladium ( 4-Bromoanisole (6.16 g, 32.2 mmol) was added to a mixture of 0.56 g, 0.61 mmol) and dioxane (80 ml), and the mixture was refluxed for 22 hours. The reaction was cooled, poured into water (200 ml) and neutralized to pH 8 with saturated aqueous ammonium chloride. The precipitate was filtered, washed with water and dried. Recrystallization from ethanol gave 3.69 g (44%) of the title compound as a tan powder.
MS Calcd .: 273; Found: 274 (M + H).

7-[(4-Chlorophenyl) amino] -3- (4-methoxybenzyl) -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7-[(4-chlorophenyl) amino] -1 -Methyl-1,3-dihydro-2H-benzimidazol-2-one (0.27 g, 1.0 mmol), 4-methoxybenzyl chloride (0.17 ml, 1.20 mmol), potassium carbonate (0.21 g, 1 .50 mmol) and N, N-dimethylformamide (1 ml) were stirred at 70 ° C. for 100 minutes. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 15% ethyl acetate / n-hexane to give 0.39 g (quantitative) of the title compound as a powder.
MS Calcd .: 393; Found: 394 (M + H).
1 H NMR (CDCl 3 ) δ 3.49 (3H, s), 3.78 (3H, s), 5.02 (2H, s), 5.30 (1H, s), 6.56 (2H, d, J = 8.4 Hz), 6.80- 6.95 (4H, m), 6.97 (1H, t, J = 8.0 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.0 Hz).

7- [( 4-Chlorophenyl ) ( isopropyl ) amino] -3- (4-methoxy-benzyl) -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7-[(4-chlorophenyl) Amino] -3- (4-methoxybenzyl) -1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.118 g, 0.30 mmol), 2-bromopropane (0.056 ml, 0 Sodium hydride (16 mg, 0.60 mmol, 90% dry) was added to a mixture of .60 mmol), tetrabutylammonium iodide (small amount) and N, N-dimethylformamide (2 ml). The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (40 ml). The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed using 20-33% ethyl acetate / n-hexane to give 80.6 mg (62%) of the title compound as an oil.
MS Calcd .: 435; Found: 436 (M + H).
1 H NMR (CDCl 3 ) δ 0.96 (3H, d, J = 6.0 Hz), 1.33 (3H, d, J = 6.0 Hz), 3.30 (3H, s), 3.79 (3H, s), 4.20-4.35 ( 1H, m), 5.02 (2H, s), 6.40 (2H, d, J = 9.2 Hz), 6.77 (1H, d, J = 8.0 Hz), 6.87 (2H, d, J = 8.4 Hz), 6.92 ( 1H, d, J = 8.0 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.09 (2H, d, J = 9.2 Hz), 7.32 (2H, d, J = 8.4 Hz).

7- [( 4-Chlorophenyl ) ( isopropyl ) amino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7- [( 4-Chlorophenyl ) ( isopropyl ) amino] -3- (4 A mixture of -methoxybenzyl) -1-methyl-1,3-dihydro-2H-benzimidazol-2-one (80 mg, 0.18 mmol) and trifluoroacetic acid (3 ml) was stirred at 65 ° C. for 19 hours. The mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate solution (20 ml), and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was flash chromatographed, eluting with 33% ethyl acetate / n-hexane, to give 26.8 mg (34%) of the title compound as an oil.
MS Calcd .: 315; Found: 316 (M + H).
1 H NMR (CDCl 3 ) TM 0.98 (3H, d, J = 6.4 Hz), 1.36 (3H, d, J = 6.4 Hz), 3.28 (3H, s), 4.20-4.35 (1H, m), 6.43 ( 2H, d, J = 8.8 Hz), 6.78-6.85 (1H, m), 7.05-7.20 (4H, m), 9.09 (1H, s).

2-Chloro-N- (4-chlorophenyl) -N-isopropyl-1-methyl-1H-benzimidazol-7-amine 7- [( 4-chlorophenyl ) ( isopropyl ) amino] -1-methyl-1,3- A mixture of dihydro-2H-benzimidazol-2-one (42 mg, 0.13 mmol) and phosphorus oxychloride (1.5 ml) was stirred at 80 ° C. for 1.5 hours. The mixture was concentrated under reduced pressure, quenched with saturated aqueous sodium bicarbonate (10 ml), and extracted with ethyl acetate (20 ml). The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was flash chromatographed and eluted with 17% ethyl acetate / n-hexane to give 31.9 mg (72%) of the title compound as an oil.
1 H NMR (CDCl 3 ) δ 0.95 (3H, d, J = 6.0 Hz), 1.39 (3H, d, J = 6.0 Hz), 3.63 (3H, s), 4.30-4.40 (1H, m), 6.40 ( 2H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.0 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.70 (1H, d, J = 8.0 Hz).

N 2 - (4-chloro-2-methoxy-6-methylphenyl) -N 7 - (4- chlorophenyl) -N 7 - isopropyl-1-methyl -1H- benzimidazole-2,7-diamine hydrochloride 2- Chloro-N- (4-chlorophenyl) -N-isopropyl-1-methyl-1H-benzimidazol-7-amine (30 mg, 0.90 mmol) and 4-chloro-3-methyl-6-methoxyaniline (46 mg, 0 .27 mmol) was stirred at 120 ° C. for 19 hours. The mixture was dissolved in ethyl acetate (30 ml), washed with saturated aqueous sodium hydrogen carbonate (15 ml) and water (10 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile containing 0.1% trifluoroacetic acid / water containing 0.1% trifluoroacetic acid). The fraction was dried, dissolved in methanol (10 ml), treated with 2M hydrogen chloride diethyl ether (2 ml) solution, and then dried under reduced pressure to give 7.8 mg (19%) of the title compound as a powder. .
MS Calcd .: 468; Found: 469 (M + H).
1 H NMR (CDCl 3 ) δ 0.96 (3H, m), 1.35 (3H, m), 2.39 (3H, s), 3.08 (3H, s), 3.63 (3H, s), 4.20-4.35 (1H, m ), 6.39 (2H, d, J = 8.8 Hz), 6.74 (1H, s), 6.89 (1H, s), 7.04 (1H, d, J = 8.0 Hz), 7.10 (2H, d, J = 8.8 Hz) ), 7.40 (1H, t, J = 8.0 Hz), 7.56 (1H, d, J = 8.0 Hz), 10.64 (1H, brs).

The following compounds were prepared in a similar manner.
Table 11



Example 151
N 2 - [2- (4- chloro-2-methoxy-6-methylphenyl) amino] -1-methyl -1H- benzimidazol-7-yl] -N 1, N 1 - diethyl -N 2 - (4 -Methoxyphenyl) glycinamide hydrochloride
Ethyl N 2 - [2- (4- chloro-2-methoxy-6-methylphenyl) amino] -1-methyl -1H- benzimidazol-7-yl]-N-(4-methoxyphenyl) glycinate (20 mg, To a solution of 0.039 mmol) in methanol (0.5 ml) was added 1N sodium hydroxide (0.5 ml). The mixture was stirred at room temperature for 1.5 hours, neutralized with 1N hydrochloric acid (0.5 ml), and concentrated to dryness. To a mixture of the residue, diethylamine (0.0081 ml, 0.079 mmol) and N, N-dimethylformamide (3 ml) was added triethylamine (0.011 ml, 0.079 mmol) and O-benzotriazol-1-yl-hexafluorophosphate. N, N, N ′, N′-tetramethyluronium (22.4 mg, 0.079 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed and eluted with 20% acetone / hexanes to give the crude product. The crude product was purified by reverse phase HPLC (acetonitrile containing 0.1% trifluoroacetic acid / water containing 0.1% trifluoroacetic acid). The eluate was concentrated under reduced pressure, the residue was dissolved in methanol (2 ml), and 2M hydrogen chloride diethyl ether (2 ml) solution was added. The mixture was concentrated under reduced pressure to give 9.6 mg (46%) of the title compound as a powder.
1 H NMR (CDCl 3 ) δ 1.20-1.40 (6H, m), 2.34 (3H, s), 3.25-3.40 (7H, m), 3.59 (3H, s), 3.74 (3H, s), 4.50-4.70 (2H, m), 6.41 (2H, d, J = 8.8 Hz), 6.65 (1H, s), 6.73 (2H, d, J = 8.8 Hz), 6.83 (1H, s), 7.15-7.45 (3H, m).

Example 152
N- [2- [ (4-Chloro-2-methoxy-6-methylphenyl) amino ] -1-methyl-1H-benzimidazol-7-yl] -N- (4-chlorophenyl) acetamide hydrochloride
4 - [(4-chlorophenyl) amino] - 1 - (4-methoxybenzyl) - 3 - methyl-1,3-dihydro -2H- benzimidazol-2-one (0.393 g, 1.0 mmol), pyridine ( 0.1 ml) and acetic anhydride (10 ml) were heated at 120 ° C. for 4 days. The reaction mixture was evaporated to dryness under reduced pressure. The residue was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed eluting with 40-50% ethyl acetate / hexane to give N- (4-chlorophenyl) -N- [1- (4-methoxybenzyl) -3-methyl-2-oxo-2. , 3-Dihydro-1H-benzimidazol-4-yl] acetamide (0.388 g, quantitative) was obtained as an oil.
MS Calcd: 435; Found: 436 (M + H).
1 H NMR (CDCl 3 ) δ 2.05 (3H, s), 3.47 (3H, s), 3.79 (3H, s), 4.99 (1H, d, J = 15.6 Hz), 5.05 (1H, d, J = 15.6 Hz), 6.87 (2H, d, J = 8.4 Hz), 6.80-6.90 (1H, m), 6.90-7.10 (2H, m), 7.31 (2H, d, J = 8.4 Hz), 7.20-7.40 (4H , m).
The title compound was prepared from this compound in a manner similar to that described in Example 138.
MS Calcd: 468; Found: 469 (M + H).
1 H NMR (CDCl 3 ) δ 2.11 (3H, s), 2.37 (3H, s), 3.48 (3H, s), 3.65 (3H, s), 6.76 (1H, s), 6.82 (1H, s), 7.00-7.20 (1H, m), 7.20-7.30 (2H, m), 7.30-7.45 (3H, m), 7.50-7.65 (1H, m), 10.80 (1H, s).

The following compounds were prepared in a similar manner.
Table 12

Example 153
N 2 - (4-bromo-2-methoxy-6-methylphenyl) -N 7 - isopropyl-1-methyl -N 7 - [4- (methylsulfonyl) phenyl]-1H-benzimidazole-2,7-diamine

7-[(4-Methylsulfonyl) phenylamino] -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 7-Amino-1-methyl-1,3-dihydrobenzimidazol-2-one (0.500 g, 3.06 mmol), 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1,1′-biphenyl (0.0629 g, 0.153 mmol), tris (dibenzylidineacetone) di A mixture of palladium (0.280 g, 0.310 mmol) and dioxane (5 ml) was treated with 4-bromophenylmethylsulfone (0.860 g, 3.70 mmol) and refluxed for 3 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate (x2) and ethyl acetate-tetrahydrofuran (x2). The extract was dried over sodium sulfate and concentrated under reduced pressure. The residual solid was washed with ethyl acetate to give 525 mg of the title compound as crystals.
1 H NMR (CDCl 3 ) δ 3.09 (3H, s), 3.25 (3H, s), 6.70 (2H, d, J = 8.6 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 7.02 (1H, t, J = 8.0 Hz), 7.64 (2H, d, J = 8.6 Hz), 8.53 (1H, s), 11.01 (1H, s).
The title compound was prepared from this compound in a manner similar to that described in Example 138.
MS Calcd: 556, 558; Found: 557, 559 (M + H).
1 H NMR (CDCl 3 ) δ 1.04 (3H, d, J = 6.4 Hz), 1.44 (3H, d, J = 6.4 Hz), 2.19 (3H, s), 3.01 (3H, s), 3.49 (3H, s), 3.81 (3H, s), 4.38-4.46 (1H, m), 5.83 (1H, s), 6.61 (2H, d, J = 8.8 Hz), 6.80 (1H, d, J = 8.0 Hz), 6.93 (1H, s), 7.06 (1H, s), 7.17 (1H, t, J = 8.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.69 (2H, d, J = 8.8 Hz).

The following compounds were prepared in a similar manner.
Table 13

The compounds of Examples 156-182 shown in Table 14 were prepared in the same manner as described in Example 31.
Table 14





Example 183
N- (4-Bromo-2-methoxy-6-methylphenyl) -7- (2-ethyl-1-piperidinyl) -1-methyl-1H-benzimidazol-2-amine

7- (2-Ethyl-1-piperidinyl) -1-methyl-1,3-dihydro-2H-benzimidazol-2-one 1-ethylcyclopentene (1.0 g, 10.4 mmol) and sodium bicarbonate (0. 1 g, 1.19 mmol) in methanol (150 ml) was ozonized at -78 ° C. until TLC analysis showed that 1-ethylcyclopentene was completely consumed. The crude ozonide is 7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.5 g, 3.07 mmol) and 10% palladium on carbon (0.05 g, Degussa type; 50% Wet) directly. A hydrogen balloon was attached to the flask and stirred for 12 hours. The reaction solution was filtered through GF / F filter paper, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10% acetone / hexane to give 597 mg (75%) of the title compound.
1.29-1.44 (3H, m), 1.62-1.68 (2H, m), 1.86-1.91 (2H, m), 2.63-2.69 (1H, m), 2.77-2.82 (1H, m), 3.01-3.04 (1H , m), 3.77 (3H, s), 6.89-7.01 (3H, m), 10.08 (1H, s); MS Calcd .: 259; Found: 260 (M + H).

2-chloro-7- (2-ethyl-1-piperidinyl) -1-methyl-1H-benzimidazole 7- (2-ethyl-1-piperidinyl) -1-methyl-1,3-dihydro-2H-benzimidazole A mixture of 2-one (200 mg, 0.77 mmol) and phosphorus oxychloride (3.55 g, 23.1 mmol) was refluxed with stirring for 12 hours and concentrated to dryness under reduced pressure. The residue was purified by column chromatography eluting with 10% acetone / hexane mixture to give 192 mg (90%) of the title compound.
1 H-NMR (CD 3 OD) δ0.77 (3H, t, J = 7.5 Hz), 1.21-1.57 (4H, m), 1.67-1.81 (2H, m), 1.83-2.02 (2H, m), 2.74 (1H, t, J = 11.27 Hz), 3.03 (1H, t, J = 6.4 Hz), 3.15 (1H, d, J = 12.1 Hz), 4.41 (3H, s), 7.51-7.61 (3H, m ); MS Calcd .: 277; Found: 278 (M + H).

N- (4-Bromo-2-methoxy-6-methylphenyl) -7- (2-ethyl-1-piperidinyl) -1-methyl-1H-benzimidazol-2-amine 2-chloro-7- (2- A mixture of ethyl-1-piperidinyl) -1-methyl-1H-benzimidazole (100 mg, 0.36 mmol) and 4-bromo-2-methoxy-6-methylaniline (390 mg, 1.8 mmol) was stirred at 110 ° C. for 12 hours. Heated. The mixture was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 15% acetone / hexane mixture to give 49.3 mg (30%) of the title compound.
1 H-NMR (CDCl 3 ) δ0.73 (3H, t, J = 7.5 Hz), 1.16-1.26 (2H, m), 1.34-1.48 (2H, m), 1.62-1.65 (2H, m), 1.87 -1.95 (2H, m), 2.18 (3H, s), 2.67-2.74 (1H, m), 2.83-2.87 (1H, m), 3.09-3.12 (1H, m), 3.81 (3H, s), 4.10 (3H, s), 6.91 (1H, s), 6.95-7.04 (3H, m), 7.29 (1H, d, J = 7.5 Hz); MS Calcd .: 456; Found: 457 (M + H), 459 .

The following compounds were prepared in a similar manner.
Table 15


Example 192
N 2 - (4-bromo-2-methoxy-6-methylphenyl) -3-methyl -N 4, N 4 - dipropyl -3H- imidazo [4,5-c] pyridine-2,4-diamine trifluoroacetic acid salt
To a suspension of N 3 -methyl-1-oxypyridine-3,4-diamine 3-bromo-4-nitropyridine-1-oxide (5.00 g, 22.8 mmol) in tetrahydrofuran (THF) in 50 mL is slowly added methylamine. (2.0 M THF solution) 68.5 mL (137 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The obtained residue was dissolved in 250 mL of dichloromethane and washed with 100 mL of saturated aqueous sodium hydrogen carbonate solution and 100 mL of water. The aqueous layers were combined and extracted with 100 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3.78 g (98%) of the title compound.
1 H NMR (CDCl 3 ) δ 3.03 (d, J = 5.3 Hz, 3H), 7.48 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H) ; MS Calcd .: 169; Found: 170 (M + H).

N 3 -Methylpyridine-3,4-diamine N 3 -Methyl-1-oxypyridine-3,4-diamine 3.78 g (22.3 mmol) of nitrogen-inactivated methanol 150 mL suspension was added to Raney nickel 2 mL. (50% aqueous suspension) was added. The reaction mixture was purged with hydrogen and stirred overnight under hydrogen balloon pressure. The catalyst was removed by filtration through GFF filter paper and the filtrate was concentrated under reduced pressure to a pink residue and solidified under high vacuum to give 2.90 g (100%) of the title compound.
1 H NMR (CDCl 3 ) δ 2.89 (s, 3H), 3.48 (s, 1H), 3.99 (br s, 2H), 6.55 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.89 (d, J = 5.3 Hz, 1H); MS Calcd .: 123; Found: 124 (M + H).

3-methyl-1,3-dihydroimidazo [4,5-c] pyridin-2-one N 1 -methylpyridine-3,4-diamine 2.80 g (22.7 mmol) in THF 125 mL solution in 1,1′- Carbonyldiimidazole 4.42 g (27.3 mmol) was added and the reaction was stirred at room temperature overnight. The reaction suspension was concentrated to about 65 mL under reduced pressure, cooled in a −10 ° C. bath, filtered, and the resulting solid was washed with 25 mL of THF. The solid was dried under high vacuum to give 2.35 g (69%) of the title compound.
1 H NMR (DMSO-d 6 ) δ 3.29 (d, J = 1.2 Hz, 3H), 6.99 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 5.1 Hz, 1H), 8.28 (s, 1H), 11.27 (br s, 1H); MS Calcd .: 149; Found: 150 (M + H).

3-Methyl-4-nitro-1,3-dihydroimidazo [4,5-c] pyridin-2-one 3-Methyl-1,3-dihydroimidazo [4,5-c] pyridin-2-one To a solution of 73 g (11.6 mmol) of conc. The reaction solution was stirred for 0.5 hours at room temperature after removing the ice-cooled bath and then heated at 100 ° C. for 2 hours. The reaction solution was quenched with 300 mL of ice water, and the pH was adjusted to 9 by adding solid ammonium carbonate. The resulting suspension was filtered and the resulting solid was washed with water and dried under high vacuum to give 1.94 g (86%) of the title compound.
1 H NMR (DMSO-d 6 ) δ 2.47 (s, 3H), 7.33-7.37 (m, 1H), 8.07 (d, J = 5.1 Hz, 1H), 11.27 (br s, 1H); MS Calcd .: 194; Found: 195 (M + H).

4-Amino-3-methyl-1,3-dihydroimidazo [4,5-c] pyridin-2-one 3-Methyl-4-nitro-1,3-dihydroimidazo [4,5-c] pyridine-2 -To a suspension of 2.24 g (11.5 mmol) of nitrogen-inactivated methanol in 25 mL was added Raney nickel 0.5 mL (50% aqueous suspension). The reaction mixture was purged with hydrogen and stirred for 1 hour under hydrogen balloon pressure. 20 mL of methanol was added to the reaction suspension, the reaction suspension was purged with hydrogen, and further stirred for 2 hours under pressure of a hydrogen balloon. The catalyst was removed by filtration with GFF filter paper, and the filtrate was concentrated under reduced pressure. The residue thus obtained (1.54 g, 81%) was used in the next reaction without further purification.
MS Calcd .: 164; Found: 165 (M + H).

4-dipropylamino-3-methyl-1,3-dihydroimidazo [4,5-c] pyridin-2-one 4-amino-3-methyl-1,3-dihydroimidazo [4,5-c] pyridine To a 15 mL suspension of -2-one 750 mg (4.57 mmol) in dichloroethane was added 3.30 mL (45.7 mmol) propionaldehyde, 1.0 mL acetic acid, and 2.90 g (13.7 mmol) sodium triacetoxyhydroborate. The reaction was heated at 45 ° C. for 7.5 hours. The reaction solution was diluted with 15 mL of dichloromethane and 15 mL of water, and the aqueous layer was extracted with 15 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained (0.91 g, 80%) was used in the next reaction without further purification.
MS Calcd .: 248; Found: 249 (M + H).

(2-Chloro-3-methyl-3H-imidazo [4,5-c] pyridin-4-yl) -dipropylamine 4-dipropylamino-3-methyl-1,3-dihydroimidazo [4,5- c] A solution of 0.91 g (3.66 mmol) of pyridin-2-one in 30 mL of phosphorus oxychloride was heated at 100 ° C. overnight and then concentrated under reduced pressure. The obtained residue was quenched with water, adjusted to pH 5 with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was pulverized with acetonitrile and filtered, and the filtrate containing the desired product was concentrated under reduced pressure. The residue thus obtained (0.18 g, 18%) was used in the next reaction without further purification.
MS Calcd .: 266; Found: 267 (M + H).

N 2 - (4-bromo-2-methoxy-6-methylphenyl) -3-methyl -N 4, N 4 - dipropyl -3H- imidazo [4,5-c] pyridine-2,4-diamine trifluoroacetic acid 180 mg (0.67 mmol) of salt (2-chloro-3-methyl-3H-imidazo [4,5-c] pyridin-4-yl) -dipropylamine and 157 mg of 4-bromo-2-methoxy-6-methylaniline A mixture of (0.73 mmol) was heated at 100 ° C. for 1 hour. The reaction was cooled to room temperature and the residue was dissolved in 10 mL of dichloromethane, washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by preparative HOLC to give 4.5 mg (2% over 3 steps) of the title compound as the trifluoroacetate salt.
1 H NMR (CDCl 3 ) δ 0.87 (t, J = 7.4 Hz, 6H), 1.47-1.56 (m, 4H), 2.22 (s, 3H), 3.17 (t, J = 7.6Hz, 4H), 3.83 ( s, 3H), 3.99 (s, 3H), 4.72 (br s, 1H), 6.94 (s, 1H), 7.07 (s, 1H), 7.12 (d, J = 5.4 Hz, 1H), 8.00 (d, J = 5.4 Hz, 1H); MS Calcd .: 445; Found: 446 (M + H).

Example 193
N 2 - [2- (3- bromopropoxy) -4-chlorophenyl] -1-methyl -N 7, N 7 - dipropyl -1H- benzimidazole-2,7-diamine
To a solution of 5-chloro-2- (7-dipropylamino-1-methyl-1H-benzimidazol-2-ylamino) phenol 100 mg (0.27 mmol) in tetrahydrofuran 4 mL was added triphenylphosphine 77 mg (0.30 mmol) and diethyl. 51 mg (0.30 mmol) of azodicarboxylate was added and the reaction mixture was stirred at room temperature for 90 minutes. To the reaction mixture, 41 mg (0.30 mmol) of 3-bromopropan-1-ol was added and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with 20% ethyl acetate / hexane to give 100 mg (76%) of the title compound.
1 H NMR (CDCl 3 ) δ 0.84 (t, J = 7.2 Hz, 6H), 1.47 (q, J = 7.2 Hz, 4H), 2.40-2.47 (m, 2H), 2.98 (br s, 4H), 3.61 (t, J = 6.3 Hz, 2H), 4.07 (s, 3H), 4.28 (t, J = 6.0 Hz, 2H), 6.85 (s, 1H), 6.91 (s, 1H), 6.95 (d, J = 7.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 7.08 (t, J = 7.8, 1H), 7.36 (d, J = 7.8 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H); MS Calcd .: 492; MS Found: 493 (M + H).

Example 194
4- [5-Chloro-2-[[7- (dipropylamino) -1-methyl-1H-benzimidazol-2-yl] amino] phenoxy) butanenitrile
N 2 - [2- (3- bromopropoxy) -4-chlorophenyl] -1-methyl -N 7, N 7 - dimethyl sulfoxide 2mL of dipropyl -1H- benzimidazole-2,7-diamine 80 mg (0.16 mmol) To the solution was added 13 mg (0.19 mmol) of potassium cyanide. The reaction was stirred at room temperature for several hours, diluted with 10 mL of water and extracted twice with 10 mL of ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with 20% acetone / hexane solution to give 75 mg (100%) of the title compound. Obtained.
1 H NMR (CDCl 3 ) δ 0.84 (t, J = 7.3 Hz, 6H), 1.42-1.51 (m, 4H), 2.22-2.28 (m, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.98 (br s, 4H), 4.07 (s, 3H), 4.23 (t, J = 5.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H) , 7.02-7.09 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H); MS Calcd .: 439; MS Found: 440 (M + H).

The following compounds were prepared in a similar manner.
Table 16

Example 196
[5-Chloro-2-[[7- (dipropylamino) -1-methyl-1H-benzimidazol-2-yl] amino] phenoxy] acetonitrile
To a solution of 48 mg (0.40 mmol) of 5-chloro-2- (7-dipropylamino-1-methyl-1H-benzimidazol-2-ylamino) phenol in 5 mL of tetrahydrofuran was added 114 mg (0.59 mmol) of cesium bicarbonate and bromo Acetonitrile 50 mg (0.41 mmol) was added and the reaction was stirred at room temperature overnight. 200 mg (1.64 mmol) of bromoacetonitrile was added to the reaction and the mixture was stirred at room temperature for several hours. Next, 50 mg (0.36 mmol) of potassium carbonate was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 20% ethyl acetate / hexane solution to give 64 mg (58%) of the title compound.
1 H NMR (CDCl 3 ) δ 0.84 (t, J = 7.3 Hz, 6H), 1.42-1.52 (m, 4H), 2.99 (br s, 4H), 4.09 (s, 3H), 4.88 (s, 2H) , 6.68 (s, 1H), 6.93-6.98 (m, 2H), 7.09 (t, J = 7.8 Hz, 1H), 7.12-7.15 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H); MS Calcd .: 411; MS Found: 412 (M + H).

The compound of Example 197 shown in Table 17 was prepared in the same manner as described in Example 193.
Table 17

The compound of Example 198 shown in Table 18 was prepared in the same manner as described in Example 194.
Table 18

Example 199
4- [5-Chloro-2-[[7- (dipropylamino) -1-methyl-1H-benzimidazol-2-yl] amino] phenoxy] butyric acid
4- [5-Chloro-2-[[7- (dipropylamino) -1-methyl-1H-benzimidazol-2-yl] amino] phenoxy] butanenitrile 63 mg (0.14 mmol) ethanol 3 mL and water 1 mL To the solution was added 29 mg (0.72 mmol) of sodium hydroxide pellets, and the reaction was stirred at 75 ° C. for 48 hours. To the reaction mixture was added 75 mg (1.87 mmol) of sodium hydroxide pellets, and the reaction was stirred at 75 ° C. for 48 hours and concentrated under reduced pressure. The obtained residue was dissolved in 5 mL of water, and the pH was adjusted to 4-5 using hydrochloric acid (1N aqueous solution). The resulting suspension was filtered and the solid was washed with water and dried under high vacuum to give 46 mg (70%) of the title compound as a white solid.
MS Calcd .: 458; MS Found: 459 (M + H).

Example 200
4- [5-Chloro-2-[[7- (dipropylamino) -1-methyl-1H-benzimidazol-2-yl] amino] phenoxy] -N-methylbutanamide hydrochloride
To a suspension of 20 mg (0.044 mmol) of 4- [5-chloro-2-[[7- (dipropylamino) -1-methyl-1H-benzimidazol-2-yl] amino] phenoxy] butyric acid in 2 mL of tetrahydrofuran , Hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium (HATU) 25 mg (0.065 mmol), diisopropylethylamine 19 μL (0.11 mmol) ) And 54 μL (0.11 mmol) of methylamine (2M tetrahydrofuran solution) were added. The reaction was stirred at room temperature for 3 hours, diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC eluting with 75% ethyl acetate / hexane solution. The isolated product was washed off the silica with 100% ethyl acetate and concentrated under reduced pressure. The residue thus obtained was dissolved in methanol and hydrochloric acid (1N diethyl ether solution) was added. The resulting suspension was concentrated under reduced pressure to give 9.0 mg (44%) of the title compound as the hydrochloride salt.
1 H NMR (CDCl 3 ) δ (free form) 0.84 (t, J = 7.2 Hz, 6H), 1.43-1.52 (m, 4H), 2.23-2.28 (m, 2H), 2.31-2.34 (m, 2H) , 2.66 (d, J = 4.9 Hz, 3H), 2.99 (br s, 4H), 4.08 (t, J = 5.6 Hz, 2H), 4.16 (s, 3H), 5.54 (br s, 1H), 6.82 ( s, 1H), 6.95 (t, J = 8.0 Hz, 2H), 7.07 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H). MS Calcd .: 471; MS Found: 472 (M + H).

The following compounds were prepared in the same manner.
Table 19

Example 202
2-[(4-Bromo-2-methoxy-6-methylphenyl) amino] -N, N-diethyl-1-methyl-1H-benzimidazole-7-carboxamide hydrochloride

Methyl 2-chloro-1-methyl-1H-benzimidazole-7-carboxylate Methyl 1-methyl-2-oxo-1,3-dihydro-2H-benzimidazole-7-carboxylate 2.00 g (9.70 mmol) Was heated at 100 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 20% ethyl acetate / hexane solution to give 1.77 g (81%) of the title compound as a white solid.
1 H NMR (CDCl 3 ) δ 3.98 (s, 3H), 4.00 (s, 3H), 7.26-7.31 (m, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H). MS Calcd .: 224; MS Found: 225 (M + H).

Methyl 2-[(4-bromo-2-methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazole-7-carboxylate methyl 2-chloro-1-methyl-1H-benzimidazole-7- A mixture of 1.50 g (6.68 mmol) of carboxylate and 2.89 g (13.4 mmol) of 4-bromo-2-methoxy-6-methylphenylamine was heated at 100 ° C. for 5 days. The reaction solution was cooled and dissolved in dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with residual 4-bromo-2-methoxy-6-methylphenylamine with 100% dichloromethane and further with 30% ethyl acetate / hexane solution to give the title compound. 356 mg (13%) were obtained.
1 H NMR (CDCl 3 ) δ 2.17 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 3.97 (s, 3H), 5.96 (s, 1H), 6.94 (s, 1H), 7.05 (s, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.61-7.67 (m, 2H). MS Calcd .: 403; MS Found: 404 (M + H).

2-[(4-Bromo-2-methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazole-7-carboxylate methyl 2-[(4-Bromo-2-methoxy-6-methylphenyl) ) To a solution of amino] -1-methyl-1H-benzimidazole-7-carboxylate 150 mg (0.371 mmol) in tetrahydrofuran 5 mL and water 2.5 mL, 156 mg (3.71 mmol) of lithium hydroxide monohydrate was added. The reaction was stirred at room temperature overnight and concentrated in vacuo. The resulting residue was diluted with water and carefully adjusted to pH 4-5 with 1N aqueous hydrochloric acid. The resulting solid was filtered, washed with water and dried under high vacuum to give 112 mg (77%) of the title compound as a white solid.
MS Calcd .: 389; MS Found: 390 (M + H).

2-[(4-Bromo-2-methoxy-6-methylphenyl) amino] -N, N-diethyl-1-methyl-1H-benzimidazole-7-carboxamide hydrochloride 2-[(4-Bromo-2 -Methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazole-7-carboxylic acid 22 mg (0.056 mmol) in a tetrahydrofuran 4 mL suspension, HATU 32 mg (0.085 mmol), diisopropylethylamine 25 μL (0 .14 mmol) and 15 μL (0.14 mmol) of diethylamine were added, and the reaction solution was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue thus obtained was diluted with water and extracted with dichloromethane containing 5% methanol. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by preparative TLC eluting with 10% methanol / dichloromethane. The isolated product was washed off the silica with 5% methanol / ethyl acetate and concentrated under reduced pressure. Hydrochloric acid (1N diethyl ether solution) was added to a purified methanol solution of the title compound, and the resulting suspension was concentrated under reduced pressure to give 14 mg (58%) of the title compound as the hydrochloride salt.
1 H NMR (CDCl 3 ) δ (free form) 1 H NMR (CDCl 3 ) δ 1.11 (t, J = 7.0 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H), 2.17 (s, 3H) , 3.31 (q, J = 7.0 Hz, 2H), 3.55 (br s, 2H), 3.67 (s, 3H), 3.82 (s, 3H), 4.72 (s, 1H), 6.93-6.96 (m, 2H) , 7.05 (s, 1H), 7.10 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H). MS Calcd .: 444; MS Found: 445 (M + H).

The following compounds were prepared in a similar manner.
Table 20

Example 206
N 2 - (4-bromo-2-methoxy-6-methylphenyl) -N 7 - 1-methyl- -N 7 - [2- (methylsulfonyl) phenyl]-1H-benzimidazole-2,7-diamine
7- [[2- ( Methylsulfonyl) phenyl ] ( propyl ) amino] -3- (4-methoxybenzyl) -1-methyl-1,3-dihydro-2H-benzimidazol-2-one As described in Example 138 7- [[2- ( Methylthio) phenyl ] ( propyl ) amino] -3- (4-methoxybenzyl) -1-methyl-1,3-dihydro-2H-benzimidazole-2-prepared analogously to the process A mixture of ON (630 mg, 1.41 mmol), m-chloroperbenzoic acid (730 mg, 4.22 mmol) and acetonitrile (5 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 50% hexane / ethyl acetate solution to give 500 mg (74%) of the title compound as an oil.
MS Calcd: 479; Found: 480 (M + H).
1 H NMR (CDCl 3 ) δ 0.91 (3H, t, J = 7.4 Hz), 1.68-1.74 (2H, m), 2.35 (3H, s), 3.50-3.54 (2H, m), 3.77 (3H, s ), 3.89 (3H, s), 5.02 (2H, s), 6.20 (1H, d, J = 8.0 Hz), 6.67 (1H, t, J = 8.0 Hz), 6.74 (1H, d, J = 8.0 Hz) ), 6.84 (2H, d, J = 8.8 Hz), 7.26-7.31 (3H, m), 7.48 (1H, d, J = 8.0 Hz), 7.64-7.69 (1H, m), 8.07 (1H, dd, J = 8.0, 1.6 Hz).

The title compound was prepared from this compound in a manner similar to that described in Example 138.
MS Calcd: 556, 558; Found: 557, 559 (M + H).
1 H NMR (CDCl 3 ) δ 0.95 (3H, t, J = 7.4 Hz), 1.73-1.79 (2H, m), 2.04 (3H, s), 2.22 (3H, s), 3.58 (2H, t, J = 8.0 Hz), 3.85 (3H, s), 4.13 (3H, s), 5.95 (1H, s), 6.24 (1H, d, J = 7.8 Hz), 6.83 (1H, t, J = 7.8 Hz), 6.94 (1H, s), 7.06 (1H, s), 7.21-7.32 (2H, m), 7.49 (1H, d, J = 7.8 Hz), 7.67 (1H, t, J = 7.8 Hz), 8.07 (1H , d, J = 7.8 Hz).

Example 207
4-[[2-[(4-Bromo-2-methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazol-7-yl] (isopropyl) amino] benzonitrile

4-[(2-Chloro-1-methyl-1H-benzimidazol-7-ylamino] benzonitrile 4-[(1-Methyl-2-oxo-1,3 prepared in the same manner as described in Example 138. -Dihydro-2H-benzimidazol-7-yl) amino] benzonitrile (137 mg, 0.518 mmol) and phosphorous oxychloride (1.5 ml) were refluxed for 3 hours. Quenched with aqueous sodium bicarbonate and extracted with ethyl acetate, the extract was washed with brine, dried over magnesium sulfate and the solvent was evaporated.The residue was flash chromatographed and 25% ethyl acetate / hexane Elution with the solution gave 66 mg (45%) of the title compound.
MS Calcd .: 282; Found: 283 (M + H)
1 H NMR (CDCl 3 ) δ3.79 (3H, s), 5.97 (1H, s), 6.62 (2H, d, J = 8.6 Hz), 7.09 (1H, d, J = 7.8 Hz), 7.28 (1H , t, J = 7.8 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.66 (1H, d, J = 7.8 Hz).

4-[(2-Chloro-1-methyl-1H-benzimidazol-7-yl) (isopropyl) amino] benzonitrile 4-[(2-Chloro-1-methyl-1H-benzimidazol-7-yl) amino ] To a suspension of benzonitrile (64 mg, 0.226 mmol), tetrabutylammonium iodide (8.4 mg, 0.023 mmol) and sodium hydride (18.1 mg, 0.679 mmol, 90% dry), Bromopropane (0.07231 ml, 0.679 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 50% hexane / ethyl acetate solution to give 64 mg (84%) of the title compound.
MS Calcd .: 324; Found: 325 (M + H)
1H NMR (CDCl 3 ) δ0.96 (3H, d, J = 6.6 Hz), 1.43 (3H, d, J = 6.6 Hz), 3.58 (3H, s), 4.30-4.43 (1H, m), 6.49 ( 2H, d, J = 8.2 Hz), 7.02 (1H, d, J = 8.0 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.75 (1H, d, J = 8.0 Hz).

4-[[2-[(4-Bromo-2-methoxy-6-methylphenyl) amino] -1-methyl-1H-benzimidazol-7-yl] (isopropyl) amino] benzonitrile 4-[(2- Of chloro-1-methyl-1H-benzimidazol-7-yl) (isopropyl) amino] benzonitrile (50 mg, 0.154 mmol) and 4-bromo-2-methyl-6-methoxyaniline (100 mg, 0.46 mmol) The mixture was stirred at 120 ° C. for 3 days. The mixture was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel and eluted with 33% ethyl acetate / hexane solution. The desired fraction was concentrated under reduced pressure, and the residual solid was washed with diethyl ether-hexane to give 7.4 mg (9.5%) of the title compound.
MS Calcd .: 503, 505; Found: 504, 506 (M + H).
1 H NMR (CDCl 3 ) δ 1.03 (3H, d, J = 6.6 Hz), 1.42 (3H, d, J = 6.6 Hz), 2.18 (3H, s), 3.49 (3H, s), 3.81 (3H, s), 4.34-4.40 (1H, m), 5.82 (1H, s), 6.55 (2H, d, J = 8.6 Hz), 6.80 (1H, d, J = 7.8 Hz), 6.93 (1H, s), 7.06 (1H, s), 7.16 (1H, t, J = 7.8 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.55 (1H, d, J = 7.8 Hz).

The following compounds were prepared in the same manner.
Table 21

Experimental example 1
Measurement of inhibition rate of corticotropin releasing factor (CRF) binding Receptor binding experiments were performed using CHO cell membrane fraction expressing human CRF receptor and sheep CRF, [ 125 I] -tyr 0 ( 125 I-CRF). It was. 100 nM of test compound was added to binding assay buffer (50 mM Tris-HCl, 5 mM EDTA, 10 mM MgCl 2 , 0.05% CHAPS, 0.1% BSA, 0.5 mM PMSF, 0.1 g / ml pepstatin, 20 μg / ml leupeptin). , PH 7.5) and incubated with 1 μg of human CRF receptor expressing CHO cell membrane fraction and 50 pM 125 I-CRF. Also, to measure non-specific binding (NSB), 0.1 μM unlabeled human urocortin, 1 μg human CRF receptor-expressing CHO cell membrane fraction and 50 pM 125 I-CRF in binding assay buffer. Incubated with. After performing the binding reaction for 1 hour at room temperature, the membrane was collected with a glass filter (UniFilter plate GF-C / Perkin Elmer) by suction filtration using a cell harvester (Perkin Elmer) and ice-cooled 50 mM. Washed with Tris-HCl (pH 7.5). After the glass filter was dried, liquid scintillation cocktail (Microscinti 0, Perkin Elmer) was added and the radioactivity of 125 I-CRF remaining on the glass filter was measured using Topcount (Perkin Elmer).

  Calculate (TB-SB) / (TB-NSB) × 100 (SB: radioactivity when compound is added, TB: maximum binding radioactivity, NSB: non-specific binding radioactivity), and each test substance 1000 nM or The binding inhibition rate was obtained in the presence of 100 nM.

Table 22 shows the binding inhibition rate of each compound measured by the method described above.
Table 22

Experimental example 2
CRF antagonist activity CRF antagonist activity was obtained by measuring inhibition of adenylate cyclase activity induced by CRF. Intracellular cyclic AMP (cAMP) concentration was measured using Alpha Screen Reagent (Perkin Elmer) according to the method described in the protocol attached to the reagent. Specifically, human CRF receptor-expressing CHO cells are seeded in 96-well plates at 40000 cells / well, cultured for 24 hours, the medium is aspirated, and 100 μl assay containing 1 μM test compound and 1 nM human CRF. Buffer (20 mM HEPES, Hank's solution, 0.1% BSA, 100 μM IBMX, pH 7.2) was added. In addition, in order to measure the intracellular cAMP concentration in the steady state, a buffer containing no compound and CRF was added. After reacting at room temperature for 30 minutes, a buffer containing 1.5 μg of anti-cAMP acceptor beads was added thereto, and a buffer containing 2 μg of biotin-cAMP / streptavidin beads and 0.15% Tween 20 was added. The liquid was added, the mixture was allowed to react at room temperature for 3 hours and the luminescence was measured with Fusion (Perkin Elmer).

  The compound (I) or (Ia) of the present invention has an excellent CRF antagonistic activity and is therefore useful as a therapeutic or prophylactic agent for affective disorders, depression, anxiety and the like.

Claims (9)

  1. Formula (I):
    (Wherein ring A is represented by formula (A ′):
    Wherein X is carbon and X 1 is —NR 5 — (wherein R 5 is C 1-4 alkyl);
    R 1 is (1) an amino substituted with two substituents selected from optionally substituted C 1-4 alkyl, optionally substituted phenyl and optionally substituted pyridyl, or (2) An optionally substituted cyclic amino where the amino nitrogen of the cyclic amino does not have a carbonyl adjacent to the nitrogen;
    R 2 is an optionally substituted phenyl or an optionally substituted pyridyl;
    Y 1 , Y 2 and Y 3 are each methine optionally substituted with a halogen atom;
    W is a bond;
    Z is -NH-)
    Or a salt thereof.
  2. The compound of claim 1, wherein R 1 is amino substituted with two C 1-4 alkyl.
  3. The compound according to claim 1, wherein R 1 is optionally substituted C 1-4 alkyl and optionally substituted phenyl or optionally substituted pyridyl substituted amino.
  4. The compound according to claim 1, wherein R 1 is a 5- or 6-membered cyclic amino optionally substituted with one or more substituents.
  5. Formula (Ia) for producing a prophylactic or therapeutic agent for diseases involving CRF receptors:
    (Wherein ring A is represented by formula (A ′):
    Wherein X is carbon and X 1 is —NR 5 — (wherein R 5 is C 1-4 alkyl);
    R 1a is (1) an amino substituted with two substituents selected from optionally substituted C 1-4 alkyl, optionally substituted phenyl and optionally substituted pyridyl, or (2) Is an optionally substituted cyclic amino;
    R 2 is an optionally substituted phenyl ;
    Y 1 , Y 2 and Y 3 are each methine optionally substituted with a halogen atom;
    W is a bond;
    Z is -NH-)
    Or a salt thereof.
  6.   Use of the compound (Ia) or a salt thereof according to claim 5 for the manufacture of a preventive or therapeutic agent for affective disorder, depression, anxiety or irritable bowel syndrome.
  7.   A pharmaceutical comprising the compound according to claim 1 or a salt thereof.
  8.   A prophylactic or therapeutic agent for a disease involving a CRF receptor comprising the compound (Ia) or a salt thereof according to claim 5.
  9.   A prophylactic or therapeutic agent for affective disorder, depression, anxiety or irritable bowel syndrome, comprising compound (Ia) or a salt thereof according to claim 5.
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